Use of genes PRDX5 and GPX4 in the production of drugs for castration-resistant prostate cancer

Abstract

The present invention relates to the use of the PRDX5 and GPX4 genes in the manufacture of drugs for castration-resistant prostate cancer, and belongs to the field of biomedicine. The present invention proposes treating or supporting the treatment of castration-resistant prostate cancer by silencing or interfering with the expression of the PRDX5 and / or GPX4 genes. The present invention is the first to propose a strategy of combining siRNA with an androgen receptor antagonist to manufacture a drug for treating CRPC, and has conducted validation studies from multiple angles and dimensions. The present invention's pharmaceutical composition combining siRNA with an androgen receptor inhibitor is useful for the treatment of castration-resistant prostate cancer and effectively improves the inhibitory effect of enzalutamide on castration-resistant prostate cancer, laying the foundation for the design and clinical application of nucleic acid drugs and having important clinical therapeutic significance.

Description

[Technical Field]

[0001] The present invention relates to the field of biomedicine, specifically to the use of genes PRDX5 and GPX4 in the manufacture of drugs for castration-resistant prostate cancer. [Background technology]

[0002] Androgen deprivation therapy (ADT) is the standard treatment for advanced prostate cancer, but after an average of 1–3 years of treatment, patients eventually progress to castration-resistant prostate cancer (CRPC). CRPC refers to prostate cancer that progresses even after initial continuous androgen deprivation therapy (ADT). Since docetaxel was proven to extend overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC) in 2004, the development of drugs targeting mCRPC disease stages, such as abiraterone acetate, enzalutamide, and cabazitaxel, has transformed the current treatment landscape for these patients. However, none of these drugs can completely reverse CRPC. Therefore, finding other effective therapeutic targets has become another research hotspot in the treatment of CRPC.

[0003] Peroxiredoxin 5 (PRDX5) is the only atypical 2-cys peroxiredoxin in mammals. It is localized in mitochondria, peroxisomes, the cytoplasm, and the nucleus and is a cytoprotective antioxidant enzyme against endogenous or exogenous peroxidative attack. Studies have shown that PRDX5 is required for cancer cells to maintain activity under conditions of oxidative stress (OS), and overexpression of PRDX5 helps protect cells from apoptosis induced by OS. OS refers to a state of imbalance between oxidative and antioxidant activity in the body. This is the result of an imbalance between two opposing forces: the generation of reactive oxygen species (ROS) and antioxidant activity. This may promote pathological defects in organisms, such as cancer and diabetes, and may also damage cellular components such as DNA. ROS are produced by a variety of processes, including hydrogen peroxide (H2O2), superoxide anion (O2), and erythrocyte endothelial cells (C1C). 2- ), highly reactive oxygen species including hydroxyl radicals. In cancer cells, ROS expression levels are elevated, but antioxidants such as PRDX5 present in cancer cells can detoxify ROS, which promotes the growth and development of cancer cells. When the balance between ROS and antioxidants between cells is disrupted, the intracellular ROS threshold level increases, causing ROS-mediated apoptosis.

[0004] Phospholipid hydroperoxide glutathione peroxidase (GPX4) is an essential antioxidant peroxidase that directly reduces phospholipid peroxides, even when incorporated into membranes and lipoproteins. It also reduces fatty acid hydroperoxides, cholesterol hydroperoxides, and thymine hydroperoxides. By preventing membrane lipid peroxidation, it plays an important role in protecting cells from oxidative damage. A 2017 Nature report showed that cancer cells with high resistance to stromal therapy are selectively sensitive to ferroptosis, a type of non-apoptotic cell death caused by the iron-dependent accumulation of lipid-derived reactive oxygen species, and that this can be induced by inhibiting the lipid hydroperoxidase GPX4. The study found that sensitivity to GPX4 inhibition is a generalized sensitivity of persister cells.

[0005] Small molecule nucleic acid drugs exert their therapeutic effects through RNA interference (RNAi), which allows them to selectively target specific targets and achieve high specificity. They can also extend their drug targeting to RNA upstream of functional proteins, thereby controlling target gene expression at the post-transcriptional level. In the early stages of siRNA therapy development, many drugs were designed based on completely unmodified or slightly modified siRNAs to reach the appropriate tissues and silence target genes. These molecules can mediate gene silencing in vivo. However, these approaches have limited efficacy and potential off-target effects. Therefore, chemically modified siRNAs, such as those replacing the 2'-OH with 2'-O-methyl (2'-OMe) or 2'-methoxyethyl (2'-MOE) groups, can effectively inhibit siRNA-mediated innate immune activation, enhance activity and specificity, and reduce off-target-induced toxicity. Many chemical modifications have been established and tested to enhance siRNA efficacy and mitigate its potential toxicity. The present invention aims to prepare PRDX5 and GPX4, which are identified as effective therapeutic targets for CRPC, into modified siRNA drugs with RNA interference effects in cells and in the body of mice, thereby reducing the expression of PRDX5, GPX4, and PRDX5+GPX4 and slowing the progression of CRPC. Summary of the Invention [Problem to be solved by the invention]

[0006] The technical problem to be solved by the present invention is to discover an effective therapeutic target, provide siPRDX5, a nucleic acid drug that can effectively treat CRPC, and significantly improve the therapeutic efficacy of CRPC.

[0007] In the present invention, after extensive research and exploration, we have discovered nucleic acid drugs for treating CRPC, namely siPRDX5 and siGPX4. Research results showed that when administered to human prostate cancer LNCaP cells, mouse MyC-CaP cells, and reversible drug-resistant persister (DTP) cells formed by LNCaP and MyC-CaP cells, siPRDX5 or siGPX4 alone could reduce the expression of PRDX5 or siGPX4 in the cancer cells, while the combination of siPRDX5 and siGPX4 could reduce the expression of both PRDX5 and GPX4. Gene and protein expression were verified by q-RTPCR and Western blot assay.

[0008] In this study, we administered siPRDX5, siGPX4, or siPRDX5 + siGPX4 to LNCaP / MyC-CaP-DTP and 22Rv1 cells and examined their efficacy through CCK8 cell proliferation assays. Results showed that siPRDX5, siGPX4, or siPRDX5 + siGPX4 significantly inhibited the growth of LNCaP-DTP, MyC-CaP-DTP, and 22Rv1 cells. Furthermore, we established a CRPC mouse model by administering continuous intragastric administration of ENZ to C-MYC-overexpressing prostate cancer mice. We then administered siPRDX5, siGPX4, or siPRDX5 + siGPX4 to the CRPC mice and examined the enzymatic activity of PRDX5 in vivo to confirm the therapeutic efficacy of this drug against prostate cancer. The results demonstrate that siPRDX5, siGPX4, or siPRDX5 + siGPX4 effectively inhibit the enzymatic activity of PRDX5, thereby effectively inhibiting the progression of prostate cancer in CRPC mice.

[0009] A first object of the present invention is to provide a double-stranded siRNA molecule described in any one of the following (A) to (C):

[0010] (A) an siRNA molecule that inhibits PRDX5 gene expression, which comprises a double-stranded siRNA molecule in which the single RNA strand shown in SEQ ID NO. 1 is complementary to the single RNA strand shown in SEQ ID NO. 2; (B) An siRNA molecule that inhibits GPX4 gene expression, which is a double-stranded siRNA molecule in which the RNA single strand shown in SEQ ID NO. 3 is complementary to the RNA single strand shown in SEQ ID NO. 4, or an siRNA in which the RNA single strand shown in SEQ ID NO. 5 is complementary to the RNA single strand shown in SEQ ID NO. 6, and (C) A composition containing (A) and (B).

[0011] In one embodiment of the present invention, at least one nucleotide in the double-stranded siRNA molecule is a modified nucleotide.

[0012] In one embodiment of the present invention, all nucleotides in the double-stranded siRNA molecule are modified nucleotides.

[0013] In one embodiment of the invention, the modification is phosphorothioate, 2'-F, 2'-OMe, 2'-Ara-F, 2'-O-MOE, m 6 A or m 5 C.

[0014] In one embodiment of the present invention, the modification is any one of the following (1) to (7): TIFF2025538062000002.tif47170(1) Phosphorothioate (PS, Rp isomer)

[0015] TIFF2025538062000003.tif45170(2)2'-Deoxy-2'-fluoro (2'-F)

[0016] TIFF2025538062000004.tif45170(3)2'-O-methyl (2'-OMe)

[0017] TIFF2025538062000005.tif45170(4)2'-Arabino-fluoro (2'-Ara-F)

[0018] TIFF2025538062000006.tif49170(5)2'-O-Methoxymethyl (2'-O-MOE)

[0019] TIFF2025538062000007.tif58170(6)N6'-methyladenosine (m 6 A)

[0020] TIFF2025538062000008.tif59170(7)5'-methylcytidine (m 5 C)

[0021] In one embodiment of the present invention, the double-stranded siRNA molecule is any one of (A1) to (A16), (B1) to (B16), and (C1) to (C16), of which (A1) to (A16) are double-stranded siRNAs modified with siPRDX5, and (B1) to (B16) and (C1) to (C16) are double-stranded siRNAs modified with siGPX4.

[0022] (A1): 5' (C)-[A]-(G)[A](C)[U](U)[A](UUA)[C](U)[A](G)[A](U)[G](A)[U](T) 3'; 5' [A]-(A)-[U](C)[A](U)[C](U)[A](G)[UAA](U)[A](A)[G](U)[C](U)[G]-[U]-[C] 3'; (A2) 5' (C)-[ A ]-(G)[ A ](C)[ U ](U)[ A ](UUA)[ C ](U)[ A ](G)[ A ](U)[ G ](A)[ U ](T) 3'; 5' [A ]-(A)-[ U ](C)[ A ](U)[ C ](U)[ A ](G)[ UAA ](U)[ A ](A)[ G ](U)[ C ](U)[ G ]-[ U ]-[ C ] 3’; (A3) 5’ ( C )-[A]-( G )[A]( C )[U]( U )[A]( UUA )[C]( U )[A]( G )[A]( U )[G]( A )[U]( T ) 3’; 5’ [A]-( A )-[U]( C )[A]( U )[C]( U )[A]( G )[UAA]( U )[A]( A )[G]( U )[C]( U )[G]-[U]-[C] 3’; (A4) 5’ ( C )-[ A ]-( G )[ A ]( C )[ U ]( U )[ A ]( UUA )[ C ]( U )[ A ]( G )[ A ]( U )[ G ]( A )[ U ]( T ) 3’; 5’ [ A ]-( A )-[U ]( C )[ A ]( U )[ C ]( U )[ A ]( G )[ UAA ]( U )[ A ]( A )[ G ]( U )[ C ]( U )[ G ]-[ U ]-[ C ] 3'; (A5) 5' (C)-[A*]-(G)[A*](C)[U](U)[A*](UUA*)[C](U)[A*](G)[A*](U)[G](A*)[U](T) 3'; 5' [A*]-(A*)-[U](C)[A*](U)[C](U)[A*](G)[UA*A*](U)[A*](A*)[G](U)[C](U)[G]-[U]-[C] 3'; (A6) 5' (C')-[A]-(G)[A](C')[U](U)[A](UUA)[C'](U)[A](G)[A](U)[G](A)[U](T) 3'; 5' [A]-(A)-[U](C')[A](U)[C'](U)[A](G)[UAA](U)[A](A)[G](U)[C'](U)[G]-[U]-[C'] 3'; (A7) 5' (C)-[ A *]-(G)[ A *](C)[ U ](U)[ A *](US*)[ C ](U)[ A *](G)[ A *](U)[ G ](A*)[ U ](T) 3'; 5'[ A *]-(A*)-[ U ](C)[ A *](U)[ C ](U)[ A*](G)[ UA * A *](U)[ A *](A*)[ G ](U)[ C ](U)[ G ]-[ U ]-[ C ] 3’; (A8) 5’ ( C )-[A*]-( G )[A*]( C )[U]( U )[A*]( UUA *)[C]( U )[A*]( G )[A*]( U )[G]( A *)[U]( T ) 3’; 5’ [A*]-( A *)-[U]( C )[A*]( U )[C]( U )[A*]( G )[UA*A*]( U )[A*]( A *)[G]( U )[C]( U )[G]-[U]-[C] 3’; (A9) 5’ ( C )-[ A *]-( G )[ A *]( C )[ U ]( U )[ A *]( UUA *)[ C ]( U )[ A *]( G )[ A *]( U )[ G ]( A *)[ U ]( T ) 3’; 5’ [ A *]-( A *)-[ U ]( C )[ A *](U )[ C ]( U )[ A *]( G )[ UA * A *]( U )[ A *]( A *)[ G ]( U )[ C ]( U )[ G ]-[ U ]-[ C ] 3’; (A10) 5’ (C’)-[ A ]-(G)[ A ](C’)[ U ](U)[ A ](UUA)[ C ’](U)[ A ](G)[ A ](U)[ G ](A)[ U ](T) 3’; 5’ [ A ]-(A)-[ U ](C’)[ A ](U)[ C ’](U)[ A ](G)[ UAA ](U)[ A ](A)[ G ](U)[ C ’](U)[ G ]-[ U ]-[ C ’] 3’; (A11) 5’ ( C ’)-[A]-( G )[A]( C ’)[U]( U )[A]( UUA )[C’]( U )[A]( G )[A]( U )[G]( A )[U]( T ) 3’; 5’ [A]-( A )-[U]( C ’)[A]( U)[C’]( U )[A]( G )[UAA]( U )[A]( A )[G]( U )[C’]( U )[G]-[U]-[C’] 3’; (A12) 5’ ( C ’)-[ A ]-( G )[ A ]( C ’)[ U ]( U )[ A ]( UUA )[ C ’]( U )[ A ]( G )[ A ]( U )[ G ]( A )[ U ]( T ) 3’; 5’ [ A ]-( A )-[ U ]( C ’)[ A ]( U )[ C ’]( U )[ A ]( G )[ UAA ]( U )[ A ]( A )[ G ]( U )[ C ’]( U )[ G ]-[ U ]-[ C ’] 3’; (A13) 5’ (C’)-[A*]-(G)[A*](C’)[U](U)[A*](UUA*)[C’](U)[A*](G)[A*](U)[G](A*)[U](T) 3’; 5’[A*]-(A*)-[U](C’)[A*](U)[C’](U)[A*](G)[UA*A*](U)[A*](A*)[G](U)[C’](U)[G]-[U]-[C’]3’; (A14) 5’ (C’)-[ A *]-(G)[ A *](C’)[ U ](U)[ A *](UUA*)[ C ’](U)[ A *](G)[ A *](U)[ G ](A*)[ U ](T) 3’; 5’[ A *]-(A*)-[ U ](C’)[ A *](U)[ C ’](U)[ A *](G)[ UA * A *](U)[ A *](A*)[ G ](U)[ C ’](U)[ G ]-[ U ]-[ C ’]3’; (A15) 5’ ( C ’)-[A*]-( G )[A*]( C ’)[U]( U )[A*]( UUA *)[C’]( U )[A*]( G )[A*]( U )[G]( A *)[U]( T ) 3’; 5’[A*]-( A *)-[U]( C ’)[A*]( U )[C’]( U )[A*]( G )[UA*A*]( U )[A*]( A *)[G]( U )[C’]( U )[G]-[U]-[C’]3’; (A16) 5' ( C ')-[ A *]-( G )[ A *]( C ')[ U ]( U )[ A *]( UUA *)[ C ']( U )[ A *]( G )[ A *]( U )[ G ]( A *)[ U ]( T ) 3'; 5'[ A *]-( A *)–[ U ]( C ')[ A *]( U )[ C ']( U )[ A *]( G )[ UA * A *]( U )[ A *]( A *)[ G ]( U )[ C ']( U )[ G ]–[ U ]–[ C ']3'; (B1) 5' (A)-[C]-(A)[A](C)[G](U)[C](AAA)[U](U)[C](G)[A](U)[A](U)[G](U) 3'; 5' [A]-(C)-[A](U)[A](U)[C](G)[A](A)[UUU](G)[A](C)[G](U)[U](G)[U]-[A]-[C] 3'; (B2) 5′ (A)–[ C ]-(YOUR)[ A ](C)[ G ](HER)[ C ](AAA)[U ](THE)[ C ](G)[ A ](THE)[ A ](THE)[ G ](U) 3'; 5' [ A ]-(C)-[ A ](THE)[ A ](THE)[ C ](G)[ A ](WITH)[ UUU ](G)[ A ](C)[ G ](THE)[ U ](G)[ U ]-[ A ]-[ C ] 3'; (B3) 5' ( A )-[C]-( A )[WITH]( C )[G]( U )[C]( AAA )[THE]( U )[C]( G )[WITH]( U )[WITH]( U )[G]( U ) 3'; 5' [A]-( C )-[WITH]( U )[WITH]( U )[C]( G )[WITH]( A )[UUU]( G )[WITH]( C )[G]( U )[THE]( G )[U]-[A]-[C] 3'; (B4) 5' ( A )-[ C ]-( A )[ A ]( C )[ G ]( U )[ C ]( AAA )[ U ]( U )[ C ]( G )[ A ]( U )[A ]( U )[ G ]( U ) 3’; 5’ [ A ]-( C )-[ A ]( U )[ A ]( U )[ C ]( G )[ A ]( A )[ UUU ]( G )[ A ]( C )[ G ]( U )[ U ]( G )[ U ]-[ A ]-[ C ] 3’; (B5) 5’ (A*)-[C]-(A*)[A*](C)[G](U)[C](A*A*A*)[U](U)[C](G)[A*](U)[A*](U)[G](U) 3’; 5’ [A*]-(C)-[A*](U)[A*](U)[C](G)[A*](A*)[UUU](G)[A*](C)[G](U)[U](G)[U]-[A*]-[C] 3’; (B6) 5’ (A)-[C’]-(A)[A](C’)[G](U)[C’](AAA)[U](U)[C’](G)[A](U)[A](U)[G](U) 3’; 5’ [A]-(C’)-[A](U)[A](U)[C’](G)[A](A)[UUU](G)[A](C’)[G](U)[U](G)[U]-[A]-[C’] 3’; (B7) 5’ (A*)-[ C ]-(A*)[ A *](C)[ G ](U)[ C ](A*A*A*)[ U ](U)[ C ](G)[ A *](U)[ A *](U)[ G](U) 3'; 5' [ A *]-(W)-[ A *](U)[ A *](U)[ C ](G)[ A *](THE*)[ UUU ](G)[ A *](W)[ G ](U)[ U ](G)[ U ]-[ A *]-[ C ] 3'; (B8) 5' ( A *)-[W]-( A *)[THE*]( C )[G]( U )[W]( A * A * A *)[U]( U )[W]( G )[THE*]( U )[THE*]( U )[G]( U ) 3'; 5' [A*]-( C )-[THE*]( U )[THE*]( U )[W]( G )[THE*]( A *)[UUU]( G )[THE*]( C )[G]( U )[U]( G )[U]-[A*]-[C] 3'; (B9) 5' ( A *)-[ C ]-( A *)[ A *]( C )[ G ]( U )[ C ]( A * A * A *)[ U ]( U )[ C ]( G )[ A *]( U )[A *]( U )[ G ]( U ) 3’; 5’ [ A *]-( C )-[ A *]( U )[ A *]( U )[ C ]( G )[ A *]( A *)[ UUU ]( G )[ A *]( C )[ G ]( U )[ U ]( G )[ U ]-[ A *]-[ C ] 3’; (B10) 5’ (A)-[ C ’]-(A)[ A ](C’)[ G ](U)[ C ’](AAA)[ U ](U)[ C ’](G)[ A ](U)[ A ](U)[ G ](U) 3’; 5’ [ A ]-(C’)-[ A ](U)[ A ](U)[ C ’](G)[ A ](A)[ UUU ](G)[ A ](C’)[ G ](U)[ U ](G)[ U ]-[ A ]-[ C ’] 3’; (B11) 5’ ( A )-[C’]-( A )[A]( C ’)[G]( U )[C’]( AAA )[U]( U)[C’]( G )[A]( U )[A]( U )[G]( U ) 3’; 5’ [A]-( C ’)-[A]( U )[A]( U )[C’]( G )[A]( A )[UUU]( G )[A]( C ’)[G]( U )[U]( G )[U]-[A]-[C’] 3’; (B12) 5’ ( A )-[ C ’]-( A )[ A ]( C ’)[ G ]( U )[ C ’]( AAA )[ U ]( U )[ C ’]( G )[ A ]( U )[ A ]( U )[ G ]( U ) 3’; 5’ [ A ]-( C ’)-[ A ]( U )[ A ]( U )[ C ’]( G )[ A ]( A )[ UUU ]( G )[ A ]( C ’)[ G ]( U )[ U ]( G )[ U ]-[ A ]-[ C ’] 3’; (B13) 5’ (A*)-[C’]-(A*)[A*](C’)[G](U)[C’](A*A*A*)[U](U)[C’](G)[A*](U)[A*](U)[G](U) 3’; 5’ [A*]-(C’)-[A*](U)[A*](U)[C’](G)[A*](A*)[UUU](G)[A*](C’)[G](U)[U](G)[U]-[A*]-[C’] 3’; (B14) 5’ (A*)-[ C ’]-(A*)[ A *](C’)[ G ](U)[ C ’](A*A*A*)[ U ](U)[ C ’](G)[ A *](U)[ A *](U)[ G ](U) 3’; 5’ [ A *]-(C’)-[ A *](U)[ A *](U)[ C ’](G)[ A *](A*)[ UUU ](G)[ A *](C’)[ G ](U)[ U ](G)[ U ]-[ A *]-[ C ’] 3’; (B15) 5’ ( A *)-[C’]-( A *)[A*]( C ’)[G]( U )[C’]( A * A * A *)[U]( U )[C’]( G )[A*]( U )[A*]( U )[G]( U ) 3’; 5’ [A*]-( C ’)-[A*]( U )[A*]( U )[C’]( G )[A*](A *)[UUU]( G )[A*]( C ')[G]( U )[U]( G )[U]-[A*]-[C'] 3'; (B16) 5' ( A *)-[ C ']-( A *)[ A *]( C ')[ G ]( U )[ C ']( A * A * A *)[ U ]( U )[ C ']( G )[ A *]( U )[ A *]( U )[ G ]( U ) 3'; 5' [ A *]-( C ')-[ A *]( U )[ A *]( U )[ C ']( G )[ A *]( A *)[ UUU ]( G )[ A *]( C ')[ G ]( U )[ U ]( G )[ U ]-[ A *]-[ C '] 3'; (C1) 5' (G)-[U]-(G)[A](G)[G](C)[A](AGA)[C](C)[G](A)[A](G)[U](A)[A](A) 3'; 5’ [U]-(U)-[U](A)[C](U)[U](C)[G](G)[UCU](U)[G](C)[C](U)[C](A)[C]-[U]-[G] 3’; (C2) 5’ (G)-[ U ]-(G)[ A ](G)[ G ](C)[ A ](AGA)[ C ](C)[ G ](A)[ A ](G)[ U ](A)[ A ](A) 3’; 5’ [ U ]-(U)-[ U ](A)[ C ](U)[ U ](C)[ G ](G)[ UCU ](U)[ G ](C)[ C ](U)[ C ](A)[ C ]-[ U ]-[ G ] 3’; (C3) 5’ ( G )-[U]-( G )[A]( G )[G]( C )[A]( AGA )[C]( C )[G]( A )[A]( G )[U]( A )[A]( A ) 3’; 5’ [U]-( U )-[U]( A )[C]( U )[U]( C )[G]( G )[UCU]( U )[G]( C )[C]( U )[C]( A )[C]-[U]-[G] 3’; (C4) 5’ ( G )-[ U ]-(G )[ A ]( G )[ G ]( C )[ A ]( AGA )[ C ]( C )[ G ]( A )[ A ]( G )[ U ]( A )[ A ]( A ) 3’; 5’ [ U ]-( U )-[ U ]( A )[ C ]( U )[ U ]( C )[ G ]( G )[ UCU ]( U )[ G ]( C )[ C ]( U )[ C ]( A )[ C ]-[ U ]-[ G ] 3’; (C5) 5’ (G)-[U]-(G)[A*](G)[G](C)[A*](A*GA*)[C](C)[G](A*)[A*](G)[U](A*)[A*](A*) 3’; 5’ [U]-(U)-[U](A*)[C](U)[U](C)[G](G)[UCU](U)[G](C)[C](U)[C](A*)[C]-[U]-[G] 3’; (C6) 5’ (G)-[U]-(G)[A](G)[G](C’)[A](AGA)[C’](C’)[G](A)[A](G)[U](A)[A](A) 3’; 5’ [U]-(U)-[U](A)[C’](U)[U](C’)[G](G)[UC’U](U)[G](C’)[C’](U)[C’](A)[C’]-[U]-[G] 3’; (C7) 5’ (G)-[ U ]-(G)[ A *](G)[ G ](C)[ A *](A*GA*)[ C ](C)[ G ](A*)[ A *](G)[ U ](A*)[ A *](A*) 3’; 5’ [ U ]-(U)-[ U ](A*)[ C ](U)[ U ](C)[ G ](G)[ UCU ](U)[ G ](C)[ C ](U)[ C ](A*)[ C ]-[ U ]-[ G ] 3’; (C8) 5’ ( G )-[U]-( G )[A*]( G )[G]( C )[A*]( A * GA *)[C]( C )[G]( A *)[A*]( G )[U]( A *)[A*]( A *) 3’; 5’ [U]-( U )-[U]( A *)[C]( U )[U]( C )[G]( G )[UCU]( U )[G]( C )[C]( U )[C]( A *)[C]-[U]-[G] 3’; (C9) 5’ ( G )-[ U ]-( G )[ A *]( G )[ G ](C )[ A *]( A * GA *)[ C ]( C )[ G ]( A *)[ A *]( G )[ U ]( A *)[ A *]( A *) 3’; 5’ [ U ]-( U )-[ U ]( A *)[ C ]( U )[ U ]( C )[ G ]( G )[ UCU ]( U )[ G ]( C )[ C ]( U )[ C ]( A *)[ C ]-[ U ]-[ G ] 3’; (C10) 5’ (G)-[ U ]-(G)[ A ](G)[ G ](C’)[ A ](AGA)[ C ’](C’)[ G ](A)[ A ](G)[ U ](A)[ A ](A) 3’; 5’ [ U ]-(U)-[ U ](A)[ C ’](U)[ U ](C’)[ G ](G)[ UC ’ U ](U)[ G ](C’)[ C ’](U)[ C ’](A)[ C ’]-[ U ]-[G ] 3’; (C11) 5’ ( G )-[U]-( G )[A]( G )[G]( C ’)[A]( AGA )[C’]( C ’)[G]( A )[A]( G )[U]( A )[A]( A ) 3’; 5’ [U]-( U )-[U]( A )[C’]( U )[U]( C ’)[G]( G )[UC’U]( U )[G]( C ’)[C’]( U )[C’]( A )[C’]-[U]-[G] 3’; (C12) 5’ ( G )-[ U ]-( G )[ A ]( G )[ G ]( C ’)[ A ]( AGA )[ C ’]( C ’)[ G ]( A )[ A ]( G )[ U ]( A )[ A ]( A ) 3’; 5’ [ U ]-( U )-[ U ]( A )[ C ’]( U )[ U ]( C ’)[ G ]( G )[ UC ’ U ]( U )[ G ](C ’)[ C ’]( U )[ C ’]( A )[ C ’]-[ U ]-[ G ] 3’; (C13) 5’ (G)-[U]-(G)[A*](G)[G](C’)[A*](A*GA*)[C’](C’)[G](A*)[A*](G)[U](A*)[A*](A*) 3’; 5’ [U]-(U)-[U](A*)[C’](U)[U](C’)[G](G)[UC’U](U)[G](C’)[C’](U)[C’](A*)[C’]-[U]-[G] 3’; (C14) 5’ (G)-[ U ]-(G)[ A *](G)[ G ](C’)[ A *](A*GA*)[ C ’](C’)[ G ](A*)[ A *](G)[ U ](A*)[ A *](A*) 3’; 5’ [ U ]-(U)-[ U ](A*)[ C ’](U)[ U ](C’)[ G ](G)[ UC ’ U ](U)[ G ](C’)[ C ’](U)[ C ’](A*)[ C ’]-[ U ]-[ G ] 3’; (C15) 5’ ( G )-[U]-( G )[A*]( G )[G]( C ’)[A*]( A * GA *)[C’]( C ’)[G]( A *)[A*](G )[U]( A *)[A*]( A *) 3'; 5' [U]-( U )-[U]( A *)[C']( U )[U]( C ')[G]( G )[UC'U]( U )[G]( C '[C']( U )[C']( A *)[C']-[U]-[G] 3'; (C16) 5' ( G )-[ U ]-( G )[ A *]( G )[ G ]( C ')[ A *]( A * GA *)[ C ']( C ')[ G ]( A *)[ A *]( G )[ U ]( A *)[ A *]( A *) 3'; 5' [ U ]-( U )-[ U ]( A *)[ C ']( U )[ U ]( C ')[ G ]( G )[ UC ' U ]( U )[ G ]( C ')[ C ']( U )[ C ']( A *)[ C ']-[ U ]-[ G ] 3'; (wherein A-, U-, C-, and G- represent phosphorothioate-modified ribonucleotides A, U, C, and G, respectively; (A), (U), (C), and (G) represent 2'-F modified ribonucleotides A, U, C, and G, respectively; [A], [U], [C], and [G] represent 2'-OMe modified ribonucleotides A, U, C, and G, respectively; (A) , (U) , (C) , and (G) represent ribonucleotides A, U, C, and G, each modified with 2'-Ara-F, [A] , [U] , [C] , and [G] represent 2'-O-MOE modified ribonucleotides A, U, C, and G, respectively; A*, U*, C*, and G* are m 6 A represents the modified ribonucleotides A, U, C, and G; A', U', C', and G' are m 5 C-modified ribonucleotides A, U, C, and G are shown.)

[0023] The second object of the present invention is to (1) a vector expressing the siRNA; (2) a host cell harboring the siRNA or the vector; (3) the siRNA, or a reagent containing (1) the vector or (2) the host cell, and (4) A pharmaceutical composition containing the siRNA The present invention aims to provide an siRNA-related biomaterial, which is any one of the following:

[0024] In one embodiment of the invention, the pharmaceutical composition further comprises an androgen or an androgen receptor inhibitor.

[0025] In one embodiment of the invention, the androgen receptor inhibitor is selected from enzalutamide (ENZ).

[0026] In one embodiment of the invention, the pharmaceutical composition comprises a pharmaceutically acceptable carrier or auxiliary material.

[0027] In one embodiment of the invention, the pharmaceutically acceptable carrier comprises a microliposome, a microcell, a metal particle, or a polymer particle.

[0028] A third object of the present invention is to provide a use of the siRNA or the biological material in the manufacture of a medicament for preventing or treating prostate cancer.

[0029] In one embodiment of the invention, the prostate cancer is aggressive prostate cancer or castration-resistant prostate cancer.

[0030] A fourth object of the present invention is to provide a method for preventing or treating prostate cancer, which comprises administering the siRNA or the biological material to a subject.

[0031] A fifth object of the present invention is to provide a method for inhibiting expression of PRDX5 and / or GPX4 genes in cells, comprising contacting an effective amount of the siRNA or the biological material with the cells, thereby inhibiting the expression of the PRDX5 and / or GPX4 genes in the cells. [Effects of the Invention]

[0032] Beneficial effects 1. This invention proposes for the first time that prostate cancer, particularly castration-resistant prostate cancer, can be improved by interfering with or silencing the expression of the PRDX5 and / or GPX4 genes, has a clear killing effect on castration-resistant prostate cancer cells, with a cell inhibition rate of up to approximately 50%, reduces prostate weight in drug-resistant CRPC mice, and suppresses tumor growth. When used in combination with the androgen receptor inhibitor ENZ, it can reduce prostate weight by approximately 40 mg, and also significantly inhibits PRDX5 enzyme activity in the prostate.

[0033] 2. This invention is the first to propose the use of nucleic acid drugs siPRDX5 and / or siPGX4 in the manufacture of CRPC therapeutics, and is of great significance in promoting the application of nucleic acid drugs in the clinical treatment of prostate cancer. Drug research takes an average of 8-10 years from compound molecule to clinical application, requiring significant human resources and material support, resulting in enormous time and financial costs. The solution of this invention can significantly shorten the time from drug discovery to clinical application. [Brief explanation of the drawings]

[0034]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

[0035] The present invention will now be further described with reference to the drawings and specific examples, which are not intended to limit the present invention in any way. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in this technical field.

[0036] Unless otherwise stated, all reagents and materials used in the following examples are commercially available.

[0037] Example 1 Synthesis of Unmodified siRNA We designed and synthesized siRNAs based on the complete mRNA sequences of human PRDX5 and GPX4. We evaluated the activity of all candidate siRNAs based on the basic siRNA design principles. All sequences were obtained from the NCBI gene database.

[0038] (1) siPRDX5 sequence: #1: 5'-AGACAGACUUAUUACUAGAUGAUTC-3'(SEQ ID NO.7) 5'-GAAUCAUCUAGUAAUAAGUCUGUCUCC-3'(SEQ ID NO.8) #2: 5' GGCCAGAUUUCUGCAAUAAACACTT-3'(SEQ ID NO.9) 5' AAGUGUUUAUUGCAGAAAUCUGGCCAA-3'(SEQ ID NO.10) #3: 5'-CAGACUUAUUACUAGAUGAUT-3'(SEQ ID NO.1) 5'-AAUCAUCUAGUAAUAAAGUCUGUC-3'(SEQ ID NO.2) (2) siGPX4 sequence: #1: 5'-GUGAGGCAAGACCGAAGUAAACUAC- 3'(SEQ ID NO.11) 5'-GUAGUUUACUUCGGUCUUGCCUCACUG-3'(SEQ ID NO.12) #2: 5'-CUACAACGUCAAAUUCGAUAUGUTC-3'(SEQ ID NO.13) 5'-GAACAUAUCGAAUUUGACGUUGUAGCC-3'(SEQ ID NO.14) #3: 5'-ACAACGUCAAAUUCGAUAUGU-3'(SEQ ID NO.3) 5'-ACAUAUCGAAUUUGACGUUGUAC-3'(SEQ ID NO.4) #4: 5'-GUGAGGCAAGACCGAAGUAAA-3'(SEQ ID NO.5) 5'-UUUACUUCGGUCUUGCCUCACUG-3'(SEQ ID NO.6) Example 2 Gene interference ability of unmodified siPRDX5 and siGPX4 on prostate cancer cells and DTP cells To screen for suitable siRNAs, the interference activity of the siRNAs designed in Example 1 was detected.

[0039] S1. 1 x 10 LNCaP and MyC-CaP cells were cultured in a 10 cm cell culture dish. 6The cells were seeded on the 50-well plate and treated with 50 μM enzalutamide (ENZ) for 9 days. The medium was replaced with fresh drug-containing medium (1640 medium containing 50 μM ENZ) every 3 days. After 9 days of treatment, the cells were harvested and designated as drug-resistant DTP cells. These cells were designated as LNCaP-DTP cells and MyC-CaP-DTP cells, respectively.

[0040] S2. LNCaP cells, MyC-CaP cells, and LNCaP-DTP cells and MyC-CaP-DTP cells collected in S1 were seeded onto 6 cm and 10 cm dishes containing fresh complete medium (1640 medium containing 10% fetal bovine serum and 1% double antibody). After attachment, they were transfected with siPRDX5 and siGPX4 designed in Example 1, followed by mRNA and protein extraction.

[0041] S3. The screening of siRNAs with interference activity was verified at the RNA and protein levels by qRT-PCR and Western blot assays.

[0042] As shown in Figures 1 and 4 and Tables 1 and 2, addition of siPRDX5 siRNA #3 significantly reduced PRDX5 expression, including both mRNA and protein levels, and addition of siGPX4 siRNA #3 and #4 significantly reduced GPX4 expression, including both mRNA and protein levels. In human prostate cancer LNCaP cells and drug-resistant LNCaP-DTP cells, PRDX5 mRNA expression levels were reduced to approximately 0.16 after siPRDX5 siRNA #3 interference, but only to approximately 0.16 after siPRDX5 siRNA #1 and #2 interference. In human prostate cancer cells LNCaP and drug-resistant LNCaP-DTP cells, the GPX4 mRNA expression level after siGPX4 #3 siRNA interference was reduced to approximately 0.21, and after siGPX4 #4 siRNA interference was reduced to approximately 0.24, whereas the GPX4 mRNA expression level after siGPX4 #1 and #2 siRNA interference was reduced to only approximately 0.73.

[0043] From the above, it was found that the siRNAs designed in Example 1 of the present invention have the ability to interfere with the expression of target genes to some extent, but among them, #3 siRNA of siPRDX5 and #3 and #4 siRNA of siGPX4 have even better ability to interfere with gene expression.

[0044] Example 3: Modification of siRNA and verification of interference ability The siPRDX5 #3 siRNA, siGPX4 #3 siRNA, and siGPX4 #4 siRNA screened in Example 2 were base-modified and synthesized in a biological company.

[0045] Here, A-, U-, C-, and G- represent phosphorothioate-modified ribonucleotides A, U, C, and G, respectively. (A), (U), (C), and (G) represent 2'-F modified ribonucleotides A, U, C, and G, respectively; [A], [U], [C], and [G] represent 2'-OMe modified ribonucleotides A, U, C, and G, respectively; (A) , (U) , (C) , and (G) represent ribonucleotides A, U, C, and G, each modified with 2'-Ara-F, [A] , [U] , [C] , and [G] represent 2'-O-MOE modified ribonucleotides A, U, C, and G, respectively; A*, U*, C*, and G* are m 6 A represents the modified ribonucleotides A, U, C, and G; A', U', C', and G' are m 5 C-modified ribonucleotides A, U, C, and G are shown.

[0046] siPRDX5#3siRNA was similar to that of siPRDX5-1~siPRDX5-16.

[0047] siPRDX5-1 5' (C)-[A]-(G)[A](C)[U](U)[A](UUA)[C](U)[A](G)[A](U)[G](A)[U](T) 3'; 5' [A]-(A)-[U](C)[A](U)[C](U)[A](G)[UAA](U)[A](A)[G](U)[C](U)[G]-[U]-[C] 3'; siPRDX5-2 5′ (C)–[ A ]–(G)[ A ](C)[ U ](U)[ A ](UUA)[ C ](U)[ A ](G)[ A ](U)[ G ](A)[ U ](T) 3′; 5' [ A ]–(A)–[ U ](C)[ A ](U)[ C ](U)[ A ](G)[ UAA ](U)[ A ](A)[ G ](U)[ C ](U)[ G ]–[ U ]–[ C ] 3'; siPRDX5-3 5' ( C )-[A]-( G )[A]( C )[U]( U )[A]( UUA )[C]( U )[A]( G )[A]( U )[G]( A )[U]( T ) 3'; 5' [A]-( A )-[U]( C )[A]( U)[C]( U )[A]( G )[UAA]( U )[A]( A )[G]( U )[C]( U )[G]-[U]-[C] 3'; siPRDX5-4 5' ( C )-[ A ]-( G )[ A ]( C )[ U ]( U )[ A ]( UUA )[ C ]( U )[ A ]( G )[ A ]( U )[ G ]( A )[ U ]( T ) 3'; 5' [ A ]-( A )-[ U ]( C )[ A ]( U )[ C ]( U )[ A ]( G )[ UAA ]( U )[ A ]( A )[ G ]( U )[ C ]( U )[ G ]-[ U ]-[ C ] 3'; siPRDX5-5 5' (C)-[A*]-(G)[A*](C)[U](U)[A*](UUA*)[C](U)[A*](G)[A*](U)[G](A*)[U](T) 3'; 5' [A*]-(A*)-[U](C)[A*](U)[C](U)[A*](G)[UA*A*](U)[A*](A*)[G](U)[C](U)[G]-[U]-[C] 3'; siPRDX5-6 5' (C')-[A]-(G)[A](C')[U](U)[A](UUA)[C'](U)[A](G)[A](U)[G](A)[U](T) 3'; 5' [A]-(A)-[U](C')[A](U)[C'](U)[A](G)[UAA](U)[A](A)[G](U)[C'](U)[G]-[U]-[C'] 3'; siPRDX5-7 5' (C)-[ A *]-(G)[ A *](C)[ U ](U)[ A *](UUA*)[ C ](U)[ A *](G)[ A *](U)[ G ](A*)[ U ](T) 3'; 5'[ A *]-(A*)-[ U ](C)[ A *](U)[ C ](U)[ A *](G)[ UA * A *](U)[ A *](A*)[ G ](U)[ C ](U)[ G ]-[ U ]-[ C ] 3'; siPRDX5-8 5' ( C )-[A*]-( G )[A*]( C )[U]( U )[A*]( UUA *)[C]( U )[A*]( G )[A*]( U )[G]( A *)[U]( T ) 3'; 5' [A*]-( A *)-[U]( C )[A*]( U )[C]( U )[A*](G )[UA*A*]( U )[A*]( A *)[G]( U )[C]( U )[G]-[U]-[C] 3'; siPRDX5-9 5' ( C )-[ A *]-( G )[ A *]( C )[ U ]( U )[ A *]( UUA *)[ C ]( U )[ A *]( G )[ A *]( U )[ G ]( A *)[ U ]( T ) 3'; 5' [ A *]-( A *)-[ U ]( C )[ A *]( U )[ C ]( U )[ A *]( G )[ UA * A *]( U )[ A *]( A *)[ G ]( U )[ C ]( U )[ G ]-[ U ]-[ C ] 3'; siPRDX5-10 5' (C')-[ A ]-(G)[ A ](C')[ U ](U)[ A ](UUA)[ C '](U)[ A ](G)[ A ](U)[ G ](A)[U ](T) 3'; 5' [ A ]-(A)-[ U ](C')[ A ](U)[ C '](U)[ A ](G)[ UAA ](U)[ A ](A)[ G ](U)[ C '](U)[ G ]-[ U ]-[ C '] 3'; siPRDX5-11 5' ( C ')-[A]-( G )[A]( C ')[U]( U )[A]( UUA )[C']( U )[A]( G )[A]( U )[G]( A )[U]( T ) 3'; 5' [A]-( A )-[U]( C ')[A]( U )[C']( U )[A]( G )[UAA]( U )[A]( A )[G]( U )[C']( U )[G]-[U]-[C'] 3'; siPRDX5-12 5' ( C ')-[ A ]-( G )[ A ]( C ')[ U ]( U )[ A ]( UUA )[ C ']( U )[ A ]( G )[ A ]( U )[ G ]( A )[ U ](T ) 3'; 5' [ A ]-( A )-[ U ]( C ')[ A ]( U )[ C ']( U )[ A ]( G )[ UAA ]( U )[ A ]( A )[ G ]( U )[ C ']( U )[ G ]-[ U ]-[ C '] 3'; siPRDX5-13 5' (C')-[A*]-(G)[A*](C')[U](U)[A*](UUA*)[C'](U)[A*](G)[A*](U)[G](A*)[U](T) 3'; 5'[A*]-(A*)-[U](C')[A*](U)[C'](U)[A*](G)[UA*A*](U)[A*](A*)[G](U)[C'](U)[G]-[U]-[C']3'; siPRDX5-14 5' (C')-[ A *]-(G)[ A *](C')[ U ](U)[ A *](UUA*)[ C '](U)[ A *](G)[ A *](U)[ G ](A*)[ U ](T) 3'; 5'[ A *]-(A*)-[ U ](C')[ A *](U)[ C '](U)[ A *](G)[ UA * A *](U)[ A *](A*)[ G ](U)[ C '](U)[G ]-[ U ]-[ C ']3'; siPRDX5-15 5' ( C ')-[A*]-( G )[A*]( C ')[U]( U )[A*]( UUA *)[C']( U )[A*]( G )[A*]( U )[G]( A *)[U]( T ) 3'; 5'[A*]-( A *)-[U]( C ')[A*]( U )[C']( U )[A*]( G )[UA*A*]( U )[A*]( A *)[G]( U )[C']( U )[G]-[U]-[C']3'; siPRDX5-16 5' ( C ')-[ A *]-( G )[ A *]( C ')[ U ]( U )[ A *]( UUA *)[ C ']( U )[ A *]( G )[ A *]( U )[ G ]( A *)[ U ]( T ) 3'; 5'[ A *]-( A *)-[ U ]( C ')[ A *]( U )[ C ']( U )[ A *]( G )[UA * A *]( U )[ A *]( A *)[ G ]( U )[ C ']( U )[ G ]-[ U ]-[ C ']3'; The sequences of siGPX4 #3 siRNA with base modifications are shown below as siGPX4-1 to siGPX4-16.

[0048] siGPX4-1 5' (A)-[C]-(A)[A](C)[G](U)[C](AAA)[U](U)[C](G)[A](U)[A](U)[G](U) 3'; 5' [A]-(C)-[A](U)[A](U)[C](G)[A](A)[UUU](G)[A](C)[G](U)[U](G)[U]-[A]-[C] 3'; siGPX4-2 5' (A)-[ C ]-(A)[ A ](C)[ G ](U)[ C ](AAA)[ U ](U)[ C ](G)[ A ](U)[ A ](U)[ G ](U) 3'; 5' [ A ]-(C)-[ A ](U)[ A ](U)[ C ](G)[ A ](A)[ UUU ](G)[ A ](C)[ G ](U)[ U ](G)[ U ]-[ A ]-[ C ] 3'; siGPX4-3 5' ( A )-[C]-( A )[A]( C)[G]( U )[C]( AAA )[U]( U )[C]( G )[A]( U )[A]( U )[G]( U ) 3’; 5’ [A]-( C )-[A]( U )[A]( U )[C]( G )[A]( A )[UUU]( G )[A]( C )[G]( U )[U]( G )[U]-[A]-[C] 3’; siGPX4-4 5’ ( A )-[ C ]-( A )[ A ]( C )[ G ]( U )[ C ]( AAA )[ U ]( U )[ C ]( G )[ A ]( U )[ A ]( U )[ G ]( U ) 3’; 5’ [ A ]-( C )-[ A ]( U )[ A ]( U )[ C ]( G )[ A ]( A )[ UUU ]( G )[ A ]( C )[ G ]( U )[ U ]( G )[ U ]-[ A ]-[ C ] 3’; siGPX4-5 5’ (A*)-[C]-(A*)[A*](C)[G](U)[C](A*A*A*)[U](U)[C](G)[A*](U)[A*](U)[G](U) 3’; 5’ [A*]-(C)-[A*](U)[A*](U)[C](G)[A*](A*)[UUU](G)[A*](C)[G](U)[U](G)[U]-[A*]-[C] 3’; siGPX4-6 5’ (A)-[C’]-(A)[A](C’)[G](U)[C’](AAA)[U](U)[C’](G)[A](U)[A](U)[G](U) 3’; 5’ [A]-(C’)-[A](U)[A](U)[C’](G)[A](A)[UUU](G)[A](C’)[G](U)[U](G)[U]-[A]-[C’] 3’; siGPX4-7 5’ (A*)-[ C ]-(A*)[ A *](C)[ G ](U)[ C ](A*A*A*)[ U ](U)[ C ](G)[ A *](U)[ A *](U)[ G ](U) 3’; 5’ [ A *]-(C)-[ A *](U)[ A *](U)[ C ](G)[ A *](A*)[ UUU ](G)[ A *](C)[ G ](U)[ U ](G)[ U ]-[ A *]-[ C ] 3’; siGPX4-8 5’ ( A *)-[C]-( A *)[A*]( C )[G]( U )[C]( A * A* A *)[U]( U )[C]( G )[A*]( U )[A*]( U )[G]( U ) 3’; 5’ [A*]-( C )-[A*]( U )[A*]( U )[C]( G )[A*]( A *)[UUU]( G )[A*]( C )[G]( U )[U]( G )[U]-[A*]-[C] 3’; siGPX4-9 5’ ( A *)-[ C ]-( A *)[ A *]( C )[ G ]( U )[ C ]( A * A * A *)[ U ]( U )[ C ]( G )[ A *]( U )[ A *]( U )[ G ]( U ) 3’; 5’ [ A *]-( C )-[ A *]( U )[ A *]( U )[ C ]( G )[ A *]( A *)[ UUU ]( G )[ A *]( C )[ G ]( U )[ U ]( G )[ U ]-[ A*]-[ C ] 3’; siGPX4-10 5’ (A)-[ C ’]-(A)[ A ](C’)[ G ](U)[ C ’](AAA)[ U ](U)[ C ’](G)[ A ](U)[ A ](U)[ G ](U) 3’; 5’ [ A ]-(C’)-[ A ](U)[ A ](U)[ C ’](G)[ A ](A)[ UUU ](G)[ A ](C’)[ G ](U)[ U ](G)[ U ]-[ A ]-[ C ’] 3’; siGPX4-11 5’ ( A )-[C’]-( A )[A]( C ’)[G]( U )[C’]( AAA )[U]( U )[C’]( G )[A]( U )[A]( U )[G]( U ) 3’; 5’ [A]-( C ’)-[A]( U )[A]( U )[C’]( G )[A]( A )[UUU]( G )[A]( C ’)[G]( U )[U]( G )[U]-[A]-[C’] 3’; siGPX4-12 5’ ( A )-[ C ’]-( A )[ A ](C ’)[ G ]( U )[ C ’]( AAA )[ U ]( U )[ C ’]( G )[ A ]( U )[ A ]( U )[ G ]( U ) 3’; 5’ [ A ]-( C ’)-[ A ]( U )[ A ]( U )[ C ’]( G )[ A ]( A )[ UUU ]( G )[ A ]( C ’)[ G ]( U )[ U ]( G )[ U ]-[ A ]-[ C ’] 3’; siGPX4-13 5’ (A*)-[C’]-(A*)[A*](C’)[G](U)[C’](A*A*A*)[U](U)[C’](G)[A*](U)[A*](U)[G](U) 3’; 5’ [A*]-(C’)-[A*](U)[A*](U)[C’](G)[A*](A*)[UUU](G)[A*](C’)[G](U)[U](G)[U]-[A*]-[C’] 3’; siGPX4-14 5’ (A*)-[ C ’]-(A*)[ A *](C’)[ G ](U)[ C ’](A*A*A*)[ U ](U)[ C ’](G)[ A *](U)[ A *](U)[ G](U) 3’; 5’ [ A *]-(C’)-[ A *](U)[ A *](U)[ C ’](G)[ A *](A*)[ UUU ](G)[ A *](C’)[ G ](U)[ U ](G)[ U ]-[ A *]-[ C ’] 3’; siGPX4-15 5’ ( A *)-[C’]-( A *)[A*]( C ’)[G]( U )[C’]( A * A * A *)[U]( U )[C’]( G )[A*]( U )[A*]( U )[G]( U ) 3’; 5’ [A*]-( C ’)-[A*]( U )[A*]( U )[C’]( G )[A*]( A *)[UUU]( G )[A*]( C ’)[G]( U )[U]( G )[U]-[A*]-[C’] 3’; siGPX4-16 5’ ( A *)-[ C ’]-( A *)[ A *]( C ’)[ G ]( U )[ C ’]( A * A * A *)[ U ]( U )[ C ’]( G )[ A*]( U )[ A *]( U )[ G ]( U ) 3'; 5' [ A *]-( C ')-[ A *]( U )[ A *]( U )[ C ']( G )[ A *]( A *)[ UUU ]( G )[ A *]( C ')[ G ]( U )[ U ]( G )[ U ]-[ A *]-[ C '] 3'; The sequences of siGPX4 #4 siRNA with base modifications are shown as siGPX4-(1) to siGPX4-(16).

[0049] siGPX4-(1) 5' (G)-[U]-(G)[A](G)[G](C)[A](AGA)[C](C)[G](A)[A](G)[U](A)[A](A) 3'; 5' [U]-(U)-[U](A)[C](U)[U](C)[G](G)[UCU](U)[G](C)[C](U)[C](A)[C]-[U]-[G] 3'; siGPX4-(2) 5' (G)-[ U ]-(G)[ A ](G)[ G ](C)[ A ](AGA)[ C ](C)[ G ](A)[ A ](G)[ U ](A)[ A ](A) 3'; 5' [ U ]-(U)-[ U ](A)[ C](U)[ U ](C)[ G ](G)[ UCU ](U)[ G ](C)[ C ](U)[ C ](A)[ C ]-[ U ]-[ G ] 3’; siGPX4-(3) 5’ ( G )-[U]-( G )[A]( G )[G]( C )[A]( AGA )[C]( C )[G]( A )[A]( G )[U]( A )[A]( A ) 3’; 5’ [U]-( U )-[U]( A )[C]( U )[U]( C )[G]( G )[UCU]( U )[G]( C )[C]( U )[C]( A )[C]-[U]-[G] 3’; siGPX4-(4) 5’ ( G )-[ U ]-( G )[ A ]( G )[ G ]( C )[ A ]( AGA )[ C ]( C )[ G ]( A )[ A ]( G )[ U ]( A )[ A ]( A ) 3’; 5’ [ U ]-( U )-[ U ]( A )[C ]( U )[ U ]( C )[ G ]( G )[ UCU ]( U )[ G ]( C )[ C ]( U )[ C ]( A )[ C ]-[ U ]-[ G ] 3’; siGPX4-(5) 5’ (G)-[U]-(G)[A*](G)[G](C)[A*](A*GA*)[C](C)[G](A*)[A*](G)[U](A*)[A*](A*) 3’; 5’ [U]-(U)-[U](A*)[C](U)[U](C)[G](G)[UCU](U)[G](C)[C](U)[C](A*)[C]-[U]-[G] 3’; siGPX4-(6) 5’ (G)-[U]-(G)[A](G)[G](C’)[A](AGA)[C’](C’)[G](A)[A](G)[U](A)[A](A) 3’; 5’ [U]-(U)-[U](A)[C’](U)[U](C’)[G](G)[UC’U](U)[G](C’)[C’](U)[C’](A)[C’]-[U]-[G] 3’; siGPX4-(7) 5’ (G)-[ U ]-(G)[ A *](G)[ G ](C)[ A *](A*GA*)[ C ](C)[ G ](A*)[ A *](G)[ U ](A*)[ A *](A*) 3’; 5’ [ U ]-(U)-[ U ](A*)[ C ](U)[ U ](C)[ G ](G)[UCU ](U)[ G ](C)[ C ](U)[ C ](A*)[ C ]-[ U ]-[ G ] 3’; siGPX4-(8) 5’ ( G )-[U]-( G )[A*]( G )[G]( C )[A*]( A * GA *)[C]( C )[G]( A *)[A*]( G )[U]( A *)[A*]( A *) 3’; 5’ [U]-( U )-[U]( A *)[C]( U )[U]( C )[G]( G )[UCU]( U )[G]( C )[C]( U )[C]( A *)[C]-[U]-[G] 3’; siGPX4-(9) 5’ ( G )-[ U ]-( G )[ A *]( G )[ G ]( C )[ A *]( A * GA *)[ C ]( C )[ G ]( A *)[ A *]( G )[ U ]( A *)[ A *]( A *) 3’; 5’ [ U ]-( U )-[ U ]( A *)[C ]( U )[ U ]( C )[ G ]( G )[ UCU ]( U )[ G ]( C )[ C ]( U )[ C ]( A *)[ C ]-[ U ]-[ G ] 3’; siGPX4-(10) 5’ (G)-[ U ]-(G)[ A ](G)[ G ](C’)[ A ](AGA)[ C ’](C’)[ G ](A)[ A ](G)[ U ](A)[ A ](A) 3’; 5’ [ U ]-(U)-[ U ](A)[ C ’](U)[ U ](C’)[ G ](G)[ UC ’ U ](U)[ G ](C’)[ C ’](U)[ C ’](A)[ C ’]-[ U ]-[ G ] 3’; siGPX4-(11) 5’ ( G )-[U]-( G )[A]( G )[G]( C ’)[A]( AGA )[C’]( C ’)[G]( A )[A]( G )[U]( A )[A]( A ) 3’; 5’ [U]-( U )-[U](A )[C’]( U )[U]( C ’)[G]( G )[UC’U]( U )[G]( C ’)[C’]( U )[C’]( A )[C’]-[U]-[G] 3’; siGPX4-(12) 5’ ( G )-[ U ]-( G )[ A ]( G )[ G ]( C ’)[ A ]( AGA )[ C ’]( C ’)[ G ]( A )[ A ]( G )[ U ]( A )[ A ]( A ) 3’; 5’ [ U ]-( U )-[ U ]( A )[ C ’]( U )[ U ]( C ’)[ G ]( G )[ UC ’ U ]( U )[ G ]( C ’)[ C ’]( U )[ C ’]( A )[ C ’]-[ U ]-[ G ] 3’; siGPX4-(13) 5’ (G)-[U]-(G)[A*](G)[G](C’)[A*](A*GA*)[C’](C’)[G](A*)[A*](G)[U](A*)[A*](A*) 3’; 5’ [U]-(U)-[U](A*)[C’](U)[U](C’)[G](G)[UC’U](U)[G](C’)[C’](U)[C’](A*)[C’]-[U]-[G] 3’; siGPX4-(14) 5’ (G)-[ U ]-(G)[ A *](G)[ G ](C’)[ A *](A*GA*)[ C ’](C’)[ G ](A*)[ A *](G)[ U ](A*)[ A *](A*) 3’; 5’ [ U ]-(U)-[ U ](A*)[ C ’](U)[ U ](C’)[ G ](G)[ UC ’ U ](U)[ G ](C’)[ C ’](U)[ C ’](A*)[ C ’]-[ U ]-[ G ] 3’; siGPX4-(15) 5’ ( G )-[U]-( G )[A*]( G )[G]( C ’)[A*]( A * GA *)[C’]( C ’)[G]( A *)[A*]( G )[U]( A *)[A*]( A *) 3’; 5’ [U]-( U )-[U]( A *)[C’]( U )[U]( C ’)[G]( G )[UC’U]( U )[G]( C ’)[C’]( U )[C’]( A*)[C’]-[U]-[G] 3’; siGPX4-(16) 5’ ( G )-[ U ]-( G )[ A *]( G )[ G ]( C ’)[ A *]( A * GA *)[ C ’]( C ’)[ G ]( A *)[ A *]( G )[ U ]( A *)[ A *]( A *) 3’; 5’ [ U ]-( U )-[ U ]( A *)[ C ’]( U )[ U ]( C ’)[ G ]( G )[ UC ’ U ]( U )[ G ]( C ’)[ C ’]( U )[ C ’]( A *)[ C ’]-[ U ]-[ G ] 3’。

[0050] As shown in Figures 2 and 3 and Tables 1 and 2, LNCaP and MyC-CaP cells, as well as their derivatives, LNCaP-DTP and MyC-CaP-DTP cells, were treated with the above-described modified siRNAs using the same method as in Example 2. The results, summarized in Tables 1 and 2, show that siPRDX5-1 to siPRDX5-16, which are sequences obtained by base-modifying the #3 siRNA of siPRDX5; siGPX4-1 to siGPX4-16, which are sequences obtained by base-modifying the #3 siRNA of siGPX4; and #4siGPX4-(1) to #4siGPX4-(16), which are sequences obtained by base-modifying the #4 siRNA of siGPX4, exhibited strong interference activity in both drug-resistant and non-drug-resistant LNCaP and MyC-CaP cells. Furthermore, #3siGPX4 exhibited higher interference efficiency than #4siGPX4. Furthermore, the interference efficiency was found to be higher in human cells than in mouse cells.

[0051] [Table 1]

[0052] [Table 2] Note: "NO." indicates the sequence number of the base modification.

[0053] Example 4 Killing ability of siPRDX5 and siGPX4 against reversibly drug-resistant prostate cancer cells Furthermore, using the CCK8 method, the modified #3siPRDX5-1 to #3siPRDX4-1 to #3siPRDX4-1 to #3siPRDX5-1-16 and #3siGPX4-1-16 synthesized in Example 3 were transfected into drug-resistant LNCaP-DTP and MyC-CaP-DTP cells, as well as 22Rv1 cells, which are themselves resistant to ENZ. This indicates that the nucleic acid drug has in vitro antitumor activity in drug-resistant cells.

[0054] 1. Experimental Method Drug-resistant cells LNCaP-DTP, MyC-CaP-DTP, and 22Rv1 cells, which are inherently ENZ-resistant, were seeded into 96-well plates containing fresh 1640 medium. After attachment, 1-16 siPRDX5, siGPX4, siPRDX5 + siGPX4, and the negative control si-neg were added. If interference was successful, the transfection mixture was aspirated and replaced with normal complete medium (1640 medium containing 10% fetal bovine serum and 1% double antibody). The cells were then cultured in an incubator for 24 h. Finally, the OD was detected by CCK8. 450 The cell viability was calculated based on the values.

[0055] 2. The results are shown in Figure 5. Figure 5A is a bar graph showing the relative viability of human prostate cancer drug-resistant LNCaP-DTP cells administered with each of siPRDX5 1 to 16 modified siRNAs. Figure 5B is a bar graph showing the relative viability of mouse prostate cancer drug-resistant MyC-CaP-DTP cells administered with each of siPRDX5-1 to 16 siRNAs. Figure 5C is a bar graph showing the relative viability of human prostate cancer ENZ drug-resistant 22Rv1 cells administered with each of siPRDX5-1 to 16 siRNAs. Figure 5D is a bar graph showing the relative viability of human prostate cancer drug-resistant LNCaP-DTP cells administered with each of siGPX4-1 to 16 siRNAs. Figure 5E is a bar graph showing the relative viability of mouse prostate cancer drug-resistant MyC-CaP-DTP cells administered with each of siGPX4-1 to 16 siRNAs. Figure 5F is a bar graph showing the relative viability of siGPX4-1 to 16 siRNAs. Figure 5G is a bar graph showing the relative viability of human prostate cancer drug-resistant cells LNCaP-DTP administered with a combination of one each of siGPX4-1 to 16 siRNA and siPRDX5-1 to 16 siRNA. Figure 5H is a bar graph showing the relative viability of mouse prostate cancer drug-resistant cells MyC-CaP-DTP administered with a combination of one each of siGPX4-1 to 16 siRNA and siPRDX5-1 to 16 siRNA. Figure 5I is a bar graph showing the relative viability of human prostate cancer drug-resistant cells 22Rv1 administered with a combination of one each of siGPX4-1 to 16 siRNA and siPRDX5-1 to 16 siRNA.

[0056] As a result, in drug-resistant DTP cells obtained by administering ENZ for nine consecutive days, the addition of ENZ did not have a significant inhibitory effect. However, the addition of the nucleic acid drugs siPRDX5 or siGPX4, which have different sequences, resulted in an inhibition rate of approximately 50% in all three cell types. Furthermore, the addition of siPRDX5 + siGPX4 showed a more potent inhibitory effect on the growth of the three cell types than the addition of one siRNA alone. This indicates that siPRDX5 and siGPX4 have a clear killing effect on drug-resistant prostate cancer cells and have the ability to inhibit the growth of drug-resistant cells, and that the combination of these two siRNAs produces a more potent effect.

[0057] Example 5: Effect of the combination of ENZ and nucleic acid drugs on a C-MYC-overexpressing prostate cancer mouse model in which resistant CRPC developed after continuous administration of ENZ Furthermore, in a mouse model of prostate cancer, we further described the effect of combining ENZ with modified #3siPRDX5 and #3siGPX4 on mice that had relapsed after chemical castration (i.e., continuous ENZ administration).

[0058] 1. Experimental Method We constructed a spontaneous prostate cancer mouse model overexpressing c-MYC (Hi-Myc). The mice progressed to the mPIN / cancer transition at 4 months of age. At this point, the mice were randomly divided into an NC control group (intragastric administration) and an ENZ treatment group. The ENZ treatment group received 10 mg / kg of ENZ intragastrically once every three days for a total of 30 days. Several mice were then sacrificed by cervical dislocation, and their prostate tumors were harvested, photographed, and weighed. ENZ significantly alleviated symptoms, with prostate weights reduced by half compared to the NC control group. The remaining mice were then treated for 60 days according to the above method. No recurrence was observed in the ENZ group, and CRPC mice were successfully obtained. After that (i.e., at 7 months of age), the mice were randomly divided into the NC control group (always intragastrically administered with the vehicle), ENZ monotherapy group, siPRDX5-1 nucleic acid drug group, ENZ and siPRDX5-1 combination group, siPRDX5-16 nucleic acid drug group, ENZ and siPRDX5-16 combination group, siGPX4-1 nucleic acid drug group, ENZ and siGPX4-1 combination group, siGPX4-16 nucleic acid drug group, ENZ and siGPX4-16 combination group, siPRDX5-16 + siGPX4-16 nucleic acid drug group, and ENZ and siPRDX5-16 + siGPX4-16 combination group, and received the corresponding treatments. While NC and ENZ were administered intragastrically, siPRDX5-1, siPRDX5-16, and siGPX4-1 and siGPX4-16 were administered via tail vein injection once every three days at 10 mg / kg ENZ and 100 nM siPRDX5-1 / 16 and siGPX4-1 / 16, respectively, for a total of 30 days. The mice were then sacrificed by cervical dislocation, and the prostate tumors were collected, photographed, weighed, and subjected to HE staining and other experiments.

[0059] 2. The results are shown in Figures 6 and 7. In Figure 6, Figure 6A shows the change in body weight of mice in each group as the administration progressed, Figure 6B is a comparison of photographs of excised prostates from mice in each group, and Figure 6C is a graph showing the change in prostate weight of mice in each group as the administration progressed, with * indicating whether the reduction in prostate weight in the other ENZ groups and the siPRDX5- and siGPX4-administered groups was significant compared to the NC group. In Figure 7, Figure 7A is an HE-stained image of prostate tissue sections from mice in each group, and Figure 7B is a bar graph showing the relative change in PRDX5 enzyme activity detected in mouse prostate tissue from each group, with * indicating whether the reduction in PRDX5 enzyme activity in the other siPRDX5- and siGPX4-administered groups was significant compared to the ENZ group.

[0060] The results for single and combined use are shown in Table 3.

[0061] [Table 3]

[0062] Combining Figure 6 and Table 3, we can see that the mean prostate weight in drug-resistant CRPC mice treated with ENZ intragastrically for 30 consecutive days was 66.67 mg, compared with 115.6 mg in the control group. After 30 days of treatment, the prostate weight in the siPRDX5-1 group decreased to 53.99 mg, while that in the siPRDX5-1 and ENZ group decreased to 49.95 mg, demonstrating the efficacy of siPRDX5 nucleic acid therapy in inhibiting tumor growth in CRPC mice. After 30 days of treatment, the prostate weight in the siGPX4-1 group was 57.81 mg, while that in the ENZ and siGPX4-1 combination group was 49.40 mg, demonstrating the efficacy of siGPX4 nucleic acid therapy in inhibiting tumor growth in CRPC mice. After 30 days of treatment, the prostate weight in the siPRDX5-16 + siGPX4-16 group decreased to 47.28 mg, while the prostate weight in the siPRDX5-16 + siGPX4-16 + ENZ combination group decreased to 39.35 mg, demonstrating the more pronounced efficacy of the siPRDX5 + siGPX4 nucleic acid drug.

[0063] The combination of ENZ with siPRDX5 or siGPX4 demonstrated superior efficacy compared with siPRDX5 or siGPX4 alone, reducing prostate weight to approximately 50 mg. Furthermore, siPRDX5 or siGPX4 alone demonstrated superior results compared with ENZ alone after drug resistance developed. siPRDX5 or siGPX4 alone demonstrated inhibitory effects on drug-resistant CRPC mice. The combination of ENZ with two nucleic acid drugs demonstrated the highest efficacy, reducing prostate weight to approximately 40 mg.

[0064] Method for detecting PRDX5 enzyme activity The thioredoxin system was used to detect PRDX5 enzyme activity. Specifically, the rate of H2O2 decomposition was measured by detecting the decrease in A340 due to the oxidation of NADPH. Experiments were performed in 150 μL reaction mixtures containing 50 mM HEPES-NaOH (pH = 7), 200 μM NADPH, 760 nM mouse TXNRD1, 11 μM human TRX, and various gradient concentrations of PRDX5. After incubation at 37°C for 5 min, the reaction was initiated by adding 500 μM H2O2.

[0065] The results of PRDX5 enzyme activity in the prostate of different groups are shown in Table 4.

[0066] [Table 4]

[0067] HE staining of tissue sections (Figure 7) showed that the combination treatment resulted in significant tumor death, regression, and fibrosis in CRPC prostate tumors. Combining the results of PRDX5 enzyme activity detection in the prostates of various groups (Table 4), we found that with continuous intragastric administration of ENZ, mice developed CRPC, with a significant increase in PRDX5 enzyme activity, reaching a relative value of 4.56. Meanwhile, with the nucleic acid drug siPRDX5-1, enzyme activity was significantly inhibited, reaching a relative value of 2.025, especially when administered in combination, reaching a relative value of 1.465. With the nucleic acid drug siGPX4-1, PRDX5 enzyme activity was also significantly inhibited, reaching a relative value of 1.810, and with the combination, reaching a relative value of 1.600. These two nucleic acid drugs demonstrated significant interference effects when used alone. When the two nucleic acid drugs were administered simultaneously, the relative enzyme activity of PRDX5 in the siPRDX5-16 + siGPX4-16 group reached 1.350, while when combined with ENZ, the enzyme activity was the lowest at 0.955, indicating that simultaneous administration of siPRDX5-16 + siGPX4-16 nucleic acid drugs can achieve the best inhibition of PRDX5 enzyme activity and the best effect of inhibiting prostate tumor formation in CRPC mice.

[0068] Although the present invention has been disclosed by the preferred embodiments, they are not intended to limit the present invention, and those skilled in the art can make various changes and modifications without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention should be determined by the following claims.

Claims

1. A double-stranded siRNA molecule characterized by being any one of the following (A) to (C): (A) An siRNA molecule that inhibits PRDX5 gene expression, comprising a double-stranded siRNA molecule in which a single RNA strand shown in SEQ ID NO. 1 is complementary to a single RNA strand shown in SEQ ID NO. 2; (B) an siRNA molecule that inhibits GPX4 gene expression, comprising a double-stranded siRNA molecule in which a single RNA strand shown in SEQ ID NO. 3 is complementary to a single RNA strand shown in SEQ ID NO. 4, or a double-stranded siRNA molecule in which a single RNA strand shown in SEQ ID NO. 5 is complementary to a single RNA strand shown in SEQ ID NO. 6; and (C) A composition containing (A) and (B).

2. The double-stranded siRNA molecule of claim 1, wherein at least one nucleotide in the double-stranded siRNA molecule is a modified nucleotide.

3. The double-stranded siRNA molecule according to claim 1 or 2, wherein all nucleotides in the double-stranded siRNA molecule are modified nucleotides.

4. The modification may be phosphorothioate, 2'-F, 2'-OMe, 2'-Ara-F, 2'-O-MOE, m ６ A or m ５ The double-stranded siRNA molecule according to claim 2 or 3, characterized in that it is at least one selected from C.

5. The double-stranded siRNA molecule according to any one of claims 2 to 4, characterized in that the double-stranded siRNA molecule is any one of the following (A1) to (C16): (A1) 5' (C) - [A] - (G) [A] (C) [U] (U) [A] (UUA) [C] (U) [A] (G) [A] (U) [G] (A) [U] (T) 3'; 5' [A] - (A) - [U] (C) [A] (U) [C] (U) [A] (G) [UAA] (U) [A] (A) [G] (U) [C] (U) [G] - [U] - [C] 3'; (A2) 5' (C) - [A] - (G) [A] (C) [U] (U) [A] (UUA) [C] (U) [A] (G) [A] (U) [G] (A) [U] (T) 3'; 5' [A] - (A) - [U] (C) [A] (U) [C] (U) [A] (G) [UAA] (U) [A] (A) [G] (U) [C] (U) [G] - [U] - [C] 3'; (A3) 5' (C) - [A] - (G) [A] (C) [U] (U) [A] (UUA) [C] (U) [A] (G) [A] (U) [G] (A) [U] (T) 3'; 5’ [A]-(A)-[U](C)[A](U)[C](U)[A](G)[UAA](U)[A](A)[G](U)[C](U)[G]-[U]-[C] 3’; (A4) 5’ (C)-[A]-(G)[A](C)[U](U)[A](UUA)[C](U)[A](G)[A](U)[G](A)[U](T) 3’; 5’ [A]-(A)-[U](C)[A](U)[C](U)[A](G)[UAA](U)[A](A)[G](U)[C](U)[G]-[U]-[C] 3’; (A5) 5’ (C)-[A*]-(G)[A*](C)[U](U)[A*](UUA*)[C](U)[A*](G)[A*](U)[G](A*)[U](T) 3’; 5’ [A*]-(A*)-[U](C)[A*](U)[C](U)[A*](G)[UA*A*](U)[A*](A*)[G](U)[C](U)[G]-[U]-[C] 3’; (A6) 5’ (C’)-[A]-(G)[A](C’)[U](U)[A](UUA)[C’](U)[A](G)[A](U)[G](A)[U](T) 3’; 5’ [A]-(A)-[U](C’)[A](U)[C’](U)[A](G)[UAA](U)[A](A)[G](U)[C’](U)[G]-[U]-[C’] 3’; (A7) 5’ (C)-[A*]-(G)[A*](C)[U](U)[A*](UUA*)[C](U)[A*](G)[A*](U)[G](A*)[U](T) 3’; 5’[A*]-(A*)-[U](C)[A*](U)[C](U)[A*](G)[UA*A*](U)[A*](A*)[G](U)[C](U)[G]-[U]-[C] 3’; (A8) 5’ (C)-[A*]-(G)[A*](C)[U](U)[A*](UUA*)[C](U)[A*](G)[A*](U)[G](A*)[U](T) 3’; 5’ [A*]-(A*)-[U](C)[A*](U)[C](U)[A*](G)[UA*A*](U)[A*](A*)[G](U)[C](U)[G]-[U]-[C] 3’; (A9) 5’ (C)-[A*]-(G)[A*](C)[U](U)[A*](UUA*)[C](U)[A*](G)[A*](U)[G](A*)[U](T) 3’; 5’ [A*]-(A*)-[U](C)[A*](U)[C](U)[A*](G)[UA*A*](U)[A*](A*)[G](U)[C](U)[G]-[U]-[C] 3’; (A10) 5’ (C’)-[A]-(G)[A](C’)[U](U)[A](UUA)[C’](U)[A](G)[A](U)[G](A)[U](T) 3’; 5’ [A]-(A)-[U](C’)[A](U)[C’](U)[A](G)[UAA](U)[A](A)[G](U)[C’](U)[G]-[U]-[C’] 3’; (A11) 5’ (C’)-[A]-(G)[A](C’)[U](U)[A](UUA)[C’](U)[A](G)[A](U)[G](A)[U](T) 3’; 5’ [A]-(A)-[U](C’)[A](U)[C’](U)[A](G)[UAA](U)[A](A)[G](U)[C’](U)[G]-[U]-[C’] 3’; (A12) 5’ (C’)-[A]-(G)[A](C’)[U](U)[A](UUA)[C’](U)[A](G)[A](U)[G](A)[U](T) 3’; 5’ [A]-(A)-[U](C’)[A](U)[C’](U)[A](G)[UAA](U)[A](A)[G](U)[C’](U)[G]-[U]-[C’] 3’; (A13) 5’ (C’)-[A*]-(G)[A*](C’)[U](U)[A*](UUA*)[C’](U)[A*](G)[A*](U)[G](A*)[U](T) 3’; 5’[A*]-(A*)-[U](C’)[A*](U)[C’](U)[A*](G)[UA*A*](U)[A*](A*)[G](U)[C’](U)[G]-[U]-[C’]3’; (A14) 5’ (C’)-[A*]-(G)[A*](C’)[U](U)[A*](UUA*)[C’](U)[A*](G)[A*](U)[G](A*)[U](T) 3’; 5’[A*]-(A*)-[U](C’)[A*](U)[C’](U)[A*](G)[UA*A*](U)[A*](A*)[G](U)[C’](U)[G]-[U]-[C’]3’; (A15) 5’ (C’)-[A*]-(G)[A*](C’)[U](U)[A*](UUA*)[C’](U)[A*](G)[A*](U)[G](A*)[U](T) 3’; 5’[A*]-(A*)-[U](C’)[A*](U)[C’](U)[A*](G)[UA*A*](U)[A*](A*)[G](U)[C’](U)[G]-[U]-[C’]3’; (A16) 5’ (C’)-[A*]-(G)[A*](C’)[U](U)[A*](UUA*)[C’](U)[A*](G)[A*](U)[G](A*)[U](T) 3’; 5’[A*]-(A*)-[U](C’)[A*](U)[C’](U)[A*](G)[UA*A*](U)[A*](A*)[G](U)[C’](U)[G]-[U]-[C’]3’; (B1) 5’ (A)-[C]-(A)[A](C)[G](U)[C](AAA)[U](U)[C](G)[A](U)[A](U)[G](U) 3’; 5’ [A]-(C)-[A](U)[A](U)[C](G)[A](A)[UUU](G)[A](C)[G](U)[U](G)[U]-[A]-[C] 3’; (B2) 5’ (A)-[C]-(A)[A](C)[G](U)[C](AAA)[U](U)[C](G)[A](U)[A](U)[G](U) 3’; 5’ [A]-(C)-[A](U)[A](U)[C](G)[A](A)[UUU](G)[A](C)[G](U)[U](G)[U]-[A]-[C] 3’; (B3) 5’ (A)-[C]-(A)[A](C)[G](U)[C](AAA)[U](U)[C](G)[A](U)[A](U)[G](U) 3’; 5’ [A]-(C)-[A](U)[A](U)[C](G)[A](A)[UUU](G)[A](C)[G](U)[U](G)[U]-[A]-[C] 3’; (B4) 5’ (A)-[C]-(A)[A](C)[G](U)[C](AAA)[U](U)[C](G)[A](U)[A](U)[G](U) 3’; 5’ [A]-(C)-[A](U)[A](U)[C](G)[A](A)[UUU](G)[A](C)[G](U)[U](G)[U]-[A]-[C] 3’; (B5) 5’ (A*)-[C]-(A*)[A*](C)[G](U)[C](A*A*A*)[U](U)[C](G)[A*](U)[A*](U)[G](U) 3’; 5’ [A*]-(C)-[A*](U)[A*](U)[C](G)[A*](A*)[UUU](G)[A*](C)[G](U)[U](G)[U]-[A*]-[C] 3’; (B6) 5’ (A)-[C’]-(A)[A](C’)[G](U)[C’](AAA)[U](U)[C’](G)[A](U)[A](U)[G](U) 3’; 5’ [A]-(C’)-[A](U)[A](U)[C’](G)[A](A)[UUU](G)[A](C’)[G](U)[U](G)[U]-[A]-[C’] 3’; (B7) 5’ (A*)-[C]-(A*)[A*](C)[G](U)[C](A*A*A*)[U](U)[C](G)[A*](U)[A*](U)[G](U) 3’; 5’ [A*]-(C)-[A*](U)[A*](U)[C](G)[A*](A*)[UUU](G)[A*](C)[G](U)[U](G)[U]-[A*]-[C] 3’; (B8) 5’ (A*)-[C]-(A*)[A*](C)[G](U)[C](A*A*A*)[U](U)[C](G)[A*](U)[A*](U)[G](U) 3’; 5’ [A*]-(C)-[A*](U)[A*](U)[C](G)[A*](A*)[UUU](G)[A*](C)[G](U)[U](G)[U]-[A*]-[C] 3’; (B9) 5’ (A*)-[C]-(A*)[A*](C)[G](U)[C](A*A*A*)[U](U)[C](G)[A*](U)[A*](U)[G](U) 3’; 5’ [A*]-(C)-[A*](U)[A*](U)[C](G)[A*](A*)[UUU](G)[A*](C)[G](U)[U](G)[U]-[A*]-[C] 3’; (B10) 5’ (A)-[C’]-(A)[A](C’)[G](U)[C’](AAA)[U](U)[C’](G)[A](U)[A](U)[G](U) 3’; 5’ [A]-(C’)-[A](U)[A](U)[C’](G)[A](A)[UUU](G)[A](C’)[G](U)[U](G)[U]-[A]-[C’] 3’; (B11) 5’ (A)-[C’]-(A)[A](C’)[G](U)[C’](AAA)[U](U)[C’](G)[A](U)[A](U)[G](U) 3’; 5’ [A]-(C’)-[A](U)[A](U)[C’](G)[A](A)[UUU](G)[A](C’)[G](U)[U](G)[U]-[A]-[C’] 3’; (B12) 5’ (A)-[C’]-(A)[A](C’)[G](U)[C’](AAA)[U](U)[C’](G)[A](U)[A](U)[G](U) 3’; 5’ [A]-(C’)-[A](U)[A](U)[C’](G)[A](A)[UUU](G)[A](C’)[G](U)[U](G)[U]-[A]-[C’] 3’; (B13) 5’ (A*)-[C’]-(A*)[A*](C’)[G](U)[C’](A*A*A*)[U](U)[C’](G)[A*](U)[A*](U)[G](U) 3’; 5’ [A*]-(C’)-[A*](U)[A*](U)[C’](G)[A*](A*)[UUU](G)[A*](C’)[G](U)[U](G)[U]-[A*]-[C’] 3’; (B14) 5’ (A*)-[C’]-(A*)[A*](C’)[G](U)[C’](A*A*A*)[U](U)[C’](G)[A*](U)[A*](U)[G](U) 3’; 5’ [A*]-(C’)-[A*](U)[A*](U)[C’](G)[A*](A*)[UUU](G)[A*](C’)[G](U)[U](G)[U]-[A*]-[C’] 3’; (B15) 5’ (A*)-[C’]-(A*)[A*](C’)[G](U)[C’](A*A*A*)[U](U)[C’](G)[A*](U)[A*](U)[G](U) 3’; 5’ [A*]-(C’)-[A*](U)[A*](U)[C’](G)[A*](A*)[UUU](G)[A*](C’)[G](U)[U](G)[U]-[A*]-[C’] 3’; (B16) 5’ (A*)-[C’]-(A*)[A*](C’)[G](U)[C’](A*A*A*)[U](U)[C’](G)[A*](U)[A*](U)[G](U) 3’; 5’ [A*]-(C’)-[A*](U)[A*](U)[C’](G)[A*](A*)[UUU](G)[A*](C’)[G](U)[U](G)[U]-[A*]-[C’] 3’; (C1) 5’ (G)-[U]-(G)[A](G)[G](C)[A](AGA)[C](C)[G](A)[A](G)[U](A)[A](A) 3’; 5’ [U]-(U)-[U](A)[C](U)[U](C)[G](G)[UCU](U)[G](C)[C](U)[C](A)[C]-[U]-[G] 3’; (C2) 5’ (G)-[U]-(G)[A](G)[G](C)[A](AGA)[C](C)[G](A)[A](G)[U](A)[A](A) 3’; 5’ [U]-(U)-[U](A)[C](U)[U](C)[G](G)[UCU](U)[G](C)[C](U)[C](A)[C]-[U]-[G] 3’; (C3) 5’ (G)-[U]-(G)[A](G)[G](C)[A](AGA)[C](C)[G](A)[A](G)[U](A)[A](A) 3’; 5’ [U]-(U)-[U](A)[C](U)[U](C)[G](G)[UCU](U)[G](C)[C](U)[C](A)[C]-[U]-[G] 3’; (C4) 5’ (G)-[U]-(G)[A](G)[G](C)[A](AGA)[C](C)[G](A)[A](G)[U](A)[A](A) 3’; 5’ [U]-(U)-[U](A)[C](U)[U](C)[G](G)[UCU](U)[G](C)[C](U)[C](A)[C]-[U]-[G] 3’; (C5) 5’ (G)-[U]-(G)[A*](G)[G](C)[A*](A*GA*)[C](C)[G](A*)[A*](G)[U](A*)[A*](A*) 3’; 5’ [U]-(U)-[U](A*)[C](U)[U](C)[G](G)[UCU](U)[G](C)[C](U)[C](A*)[C]-[U]-[G] 3’; (C6) 5’ (G)-[U]-(G)[A](G)[G](C’)[A](AGA)[C’](C’)[G](A)[A](G)[U](A)[A](A) 3’; 5’ [U]-(U)-[U](A)[C’](U)[U](C’)[G](G)[UC’U](U)[G](C’)[C’](U)[C’](A)[C’]-[U]-[G] 3’; (C7) 5’ (G)-[U]-(G)[A*](G)[G](C)[A*](A*GA*)[C](C)[G](A*)[A*](G)[U](A*)[A*](A*) 3’; 5’ [U]-(U)-[U](A*)[C](U)[U](C)[G](G)[UCU](U)[G](C)[C](U)[C](A*)[C]-[U]-[G] 3’; (C8) 5’ (G)-[U]-(G)[A*](G)[G](C)[A*](A*GA*)[C](C)[G](A*)[A*](G)[U](A*)[A*](A*) 3’; 5’ [U]-(U)-[U](A*)[C](U)[U](C)[G](G)[UCU](U)[G](C)[C](U)[C](A*)[C]-[U]-[G] 3’; (C9) 5’ (G)-[U]-(G)[A*](G)[G](C)[A*](A*GA*)[C](C)[G](A*)[A*](G)[U](A*)[A*](A*) 3’; 5’ [U]-(U)-[U](A*)[C](U)[U](C)[G](G)[UCU](U)[G](C)[C](U)[C](A*)[C]-[U]-[G] 3’; (C10) 5’ (G)-[U]-(G)[A](G)[G](C’)[A](AGA)[C’](C’)[G](A)[A](G)[U](A)[A](A) 3’; 5’ [U]-(U)-[U](A)[C’](U)[U](C’)[G](G)[UC’U](U)[G](C’)[C’](U)[C’](A)[C’]-[U]-[G] 3’; (C11) 5’ (G)-[U]-(G)[A](G)[G](C’)[A](AGA)[C’](C’)[G](A)[A](G)[U](A)[A](A) 3’; 5’ [U]-(U)-[U](A)[C’](U)[U](C’)[G](G)[UC’U](U)[G](C’)[C’](U)[C’](A)[C’]-[U]-[G] 3’; (C12) 5’ (G)-[U]-(G)[A](G)[G](C’)[A](AGA)[C’](C’)[G](A)[A](G)[U](A)[A](A) 3’; 5’ [U]-(U)-[U](A)[C’](U)[U](C’)[G](G)[UC’U](U)[G](C’)[C’](U)[C’](A)[C’]-[U]-[G] 3’; (C13) 5’ (G)-[U]-(G)[A*](G)[G](C’)[A*](A*GA*)[C’](C’)[G](A*)[A*](G)[U](A*)[A*](A*) 3’; 5’ [U]-(U)-[U](A*)[C’](U)[U](C’)[G](G)[UC’U](U)[G](C’)[C’](U)[C’](A*)[C’]-[U]-[G] 3’; (C14) 5' (G) - [U] - (G) [A*] (G) [G] (C') [A*] (A*GA*) [C'] (C') [G] (A*) [A*] (G) [U] (A*) [A*] (A*) 3'; 5' [U] - (U) - [U] (A*) [C'] (U) [U] (C') [G] (G) [UC'U] (U) [G] (C') [C'] (U) [C'] (A*) [C'] - [U] - [G] 3'; (C15) 5' (G) - [U] - (G) [A*] (G) [G] (C') [A*] (A*GA*) [C'] (C') [G] (A*) [A*] (G) [U] (A*) [A*] (A*) 3'; 5' [U] - (U) - [U] (A*) [C'] (U) [U] (C') [G] (G) [UC'U] (U) [G] (C') [C'] (U) [C'] (A*) [C'] - [U] - [G] 3'; (C16) 5' (G) - [U] - (G) [A*] (G) [G] (C') [A*] (A*GA*) [C'] (C') [G] (A*) [A*] (G) [U] (A*) [A*] (A*) 3'; 5' [U] - (U) - [U] (A*) [C'] (U) [U] (C') [G] (G) [UC'U] (U) [G] (C') [C'] (U) [C'] (A*) [C'] - [U] - [G] 3'; (wherein A-, U-, C-, and G- represent phosphorothioate-modified ribonucleotides A, U, C, and G, respectively; (A), (U), (C), and (G) represent 2'-F modified ribonucleotides A, U, C, and G, respectively; [A], [U], [C], and [G] represent 2'-OMe modified ribonucleotides A, U, C, and G, respectively; (A), (U), (C), and (G) represent 2'-Ara-F modified ribonucleotides A, U, C, and G, respectively; [A], [U], [C], and [G] represent 2'-O-MOE modified ribonucleotides A, U, C, and G, respectively; A*, U*, C*, and G* are m ６ A-modified ribonucleotides A, U, C, and G are shown; A', U', C', and G' are m ５ C-modified ribonucleotides A, U, C, and G are shown.

6. (1) a vector that expresses the siRNA; (2) a host cell containing the siRNA or the vector; (3) the siRNA, or a reagent containing (1) the vector or (2) the host cell, and (4) A pharmaceutical composition containing the siRNA. The siRNA-related biomaterial according to any one of claims 1 to 5, characterized in that it is any one of the following:

7. The biological material according to claim 6, characterized in that the pharmaceutical composition further contains an androgen or an androgen receptor inhibitor.

8. 8. The biological material according to claim 6 or 7, characterized in that the pharmaceutical composition contains a pharmaceutically acceptable carrier or auxiliary material.

9. The biomaterial of claim 8 , wherein the pharmaceutically acceptable carrier comprises a microliposome, a microcell, a metal particle, or a polymer particle.

10. Use of the siRNA according to any one of claims 1 to 5 or the biological material according to any one of claims 6 to 9 in the manufacture of a drug for preventing or treating prostate cancer.

11. The use according to claim 10, wherein the prostate cancer is advanced prostate cancer or castration-resistant prostate cancer.

12. A method for preventing or treating prostate cancer, comprising administering to a subject the siRNA according to any one of claims 1 to 5 or the biological material according to any one of claims 6 to 9.

13. A method for inhibiting the expression of PRDX5 and / or GPX4 genes in cells, comprising contacting the cells with an effective amount of the siRNA according to any one of claims 1 to 5 or the biological material according to any one of claims 6 to 9, thereby inhibiting the expression of the PRDX5 and / or GPX4 genes in the cells.

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