Application of endoperoxide combined glutamine deprivation in tumor cell metastasis inhibition medicine with ferroptosis sensitivity independent of ACSL4

Abstract

The invention provides an application of endoperoxide combined glutamine deprivation in a tumor cell metastasis inhibition drug with ferroptosis sensitivity independent of ACSL4. The technical problem that in the prior art, the ferroptosis tolerance is more beneficial to tumor cell metastasis is solved, and a new intervention strategy which is low in ferroptosis sensitivity and effectively inhibits tumor cell metastasis is developed.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and specifically relates to the application of endoperoxide combined with glutamine deprivation in tumor cell metastasis inhibitory drugs whose ferroptosis sensitivity is not dependent on ACSL4. Background Art

[0002] Ferroptosis is a form of programmed cell death that is different from apoptosis and necrosis and is caused by the accumulation of lipid peroxidation that is dependent on iron ions. It is of great significance for the development of new tumor treatment strategies. Ferroptosis and tumor metastasis, especially the epithelial-mesenchymal transition (EMT) process, are closely related to lipid metabolism.

[0003] Recent studies have shown that lipid peroxidation accumulation can promote tumor cell metastasis, and metastatic EMT cancer cells also become more sensitive to the ferroptosis pathway. In epithelial cells, cell-cell interactions mediated by E-cadherin (E-cad) can inhibit ferroptosis by activating intracellular NF2 and Hippo signaling pathways, and inhibition of this signal axis can promote ferroptosis by upregulating lipid peroxidation regulators through the transcriptional coactivator YAP. When head and neck cancer cells were treated with the classic ferroptosis inducer Rsl3, silencing the EMT marker ZEB1 reduced lipid peroxide production. In addition, phospholipids containing polyunsaturated fatty acids (PUFAs) (PUFA-PLs) are the main substrates for lipid peroxidation. Long-chain acyl-CoA synthetase 4 (ACSL4), as a key component of membrane lipid composition, is a key enzyme in the synthesis and modification of PUFA-PLs, which can induce cell sensitivity to ferroptosis and increase cell membrane fluidity. Existing studies believe that ACSL4 is an important pharmacological target for the treatment of ferroptosis-related diseases, but there are currently no compounds that directly target ACSL4. The EMT transformation process requires high levels of PUFA-PLs to increase the fluidity of the cell membrane, so this may also be the reason why EMT cancer cells become more sensitive to ferroptosis.

[0004] Glutamine (Gln) is the most abundant amino acid in the circulation and amino acid pool of humans and animals, and is also the most functional amino acid. Since cancer cells rapidly consume exogenous Gln to survive, the content of Gln in tumor cells is low. Therefore, the rapid development of tumors depends on the reprogramming and utilization of Gln to maintain their growth. Gln deprivation can upregulate Slug, the master regulator of EMT, through MEK / ERK signaling and ATF4 pathways, inducing EMT and further metastasis in cancer cells. On the other hand, Gln metabolism is also closely related to the sensitivity of cells to ferroptosis. The core sensing signaling pathway of amino acid metabolism is mTORC1, which is closely related to both EMT and ferroptosis of cancer cells. In recent years, literature has reported that β-catenin mutations in liver cancer lead to overexpression of Wnt-specific targeted GLUL, which promotes Gln synthesis by activating glutamine synthetase (GS) activity, thereby activating mTORC1 and phosphorylating its downstream targets S6K1 and 4EBP1 to increase protein synthesis. Endoperoxides are a class of organic compounds containing peroxide bridge bonds. They contain a peroxide bridge bond (OO) in their structure and exhibit a variety of properties and reactions in chemical reactions. Endoperoxides are mainly divided into 1,2-dioxane, 1,2,4-trioxane, 1,2,4,5-tetraoxane, 1,2-dioxolane and 1,2,4-trioxolane, etc., depending on the size of the ring and the position of heteroatom substitution. These endoperoxides have a variety of biological activities, such as antimalarial and antitumor, and their physical and chemical properties are relatively stable, which has attracted widespread attention.

[0005] Among them, artemisinin (ART) is a natural compound with a peroxide bridge group in its structure that is safe and reliable for the human body. In recent years, it has been found that ART can not only inhibit tumor progression, but also inhibit tumor metastasis by affecting EMT and angiogenesis. The effect of ART may also be related to Gln metabolism. Literature reports that inhibiting Gln hydrolase GLS1 can not only block the metabolic reprogramming of liver cancer cells, but also reduce the dosage of dihydroartemisinin (DHA). FINO2, as an organic endoperoxide, has a good anti-tumor effect.

[0006] Based on this, by studying the mechanism and characteristics of endoperoxide-induced ferroptosis and its effect on the EMT process of tumor cells caused by Gln deprivation, it is expected to provide new intervention strategies for inhibiting tumor cell metastasis. Summary of the invention

[0007] To this end, the technical problem to be solved by the present invention is to provide the application of endoperoxide combined with glutamine deprivation in tumor cell metastasis inhibitory drugs whose ferroptosis sensitivity is not dependent on ACSL4. The technical problem that ferroptosis tolerance is more conducive to tumor cell metastasis in the prior art is solved, and a new intervention strategy with low sensitivity to ferroptosis is developed to effectively inhibit tumor cell metastasis.

[0008] The present invention provides a technical solution: application of endoperoxide combined with glutamine deprivation in a tumor cell metastasis inhibitory drug whose ferroptosis sensitivity is independent of ACSL4, wherein the glutamine deprivation includes blocking glutamine supply and / or synthesis.

[0009] Preferably, the method further comprises an mTORC1 inhibitor, wherein the endoperoxide combined with glutamine deprivation and the mTORC1 inhibitor inhibits epithelial-mesenchymal transition of tumor cells.

[0010] Preferably, epithelial-mesenchymal transition of tumor cells is inhibited by regulating the mTORC1 signaling pathway.

[0011] Preferably, the regulation of the mTORC1 signaling pathway is upregulating the expression of the mTORC1 protein.

[0012] Preferably, the endoperoxide is a 1,2,4-trioxane type endoperoxide.

[0013] Preferably, the 1,2,4-trioxane endoperoxide is artemisinin or FINO2.

[0014] Preferably, the tumor comprises a triple-negative breast tumor.

[0015] Preferably, the tumor cell metastasis inhibitory drug comprises an effective amount of artemisinin and / or FINO2 that inhibits epithelial-mesenchymal transition of tumor cells.

[0016] Beneficial effects: The present invention provides an application of endoperoxide combined with glutamine deprivation in a tumor cell metastasis inhibitory drug whose ferroptosis sensitivity is independent of ACSL4. The characteristics of ferroptosis sensitivity mediated by endoperoxide under Gln deprivation conditions are confirmed for the first time. Based on the differential expression of ACSL4 under different Gln supply conditions, it is found that endoperoxide can be used to interfere with Gln deprivation to cause tumor cells, especially TNBC cells, to resist classical ferroptosis inducers and EMT.

[0017] For the first time, the changes in lipid metabolism caused by Gln deprivation and its relationship with EMT and ferroptosis tolerance were confirmed. The role of Gln deprivation in regulating EMT and tolerance to classical ferroptosis inducers was confirmed; and the mTORC1-mediated lipid metabolism changes were taken as the core to reveal its mechanism of action in Gln deprivation-induced tolerance to classical ferroptosis inducers and promoting EMT. This provides a new solution for inhibiting tumor cell metastasis caused by glutamine starvation therapy or interfering with glutamine metabolism in the clinic.

[0018] In the method of the present invention, 1,2,4-trioxane endoperoxides, such as ART, FINO2 endoperoxides, combined with glutamine deprivation and mTORC1 inhibitors, achieve the inhibitory effect on tumor cell metastasis by inducing ferroptosis. Compared with the classic ferroptosis inducers, the method of the present invention clarifies that 1,2,4-trioxane endoperoxides, such as ART, FINO2 combined with glutamine deprivation and mTORC1 inhibitors can be used for the treatment of breast cancer metastasis and clarifies its mechanism of action. It lays the foundation and provides new ideas for the development of effective drugs that inhibit tumor cell metastasis, especially those that inhibit tumor cell metastasis under Gln deprivation conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to make the contents of the present invention more clearly understood, the present invention is further described in detail below based on specific embodiments of the present invention in conjunction with the accompanying drawings.

[0020] Figure 1 It is a schematic diagram of the technical path of the present invention; Figure 2 Schematic diagram of the experimental results of the present invention showing that Gln deprivation induces the sensitivity of TNBC cells to ferroptosis induced by classical ferroptosis inducers; Figure 3 Schematic diagram of the experimental results of the present invention showing that Gln deprivation induces the sensitivity of TNBC cells to FINO2-induced ferroptosis; Figure 4 This is a schematic diagram of the results of the characteristics of endoperoxide-induced ferroptosis in TNBC cells in Example 1 of the present invention; Figure 5 Schematic diagram of the experimental results of the effect of endoperoxide on ACSL4-independent Gln sufficiency-mediated resistance to classical ferroptosis inducers in Example 1 A; Figure 6 Schematic diagram B of the experimental results of the effect of endoperoxide on ACSL4-independent Gln sufficiency-mediated sensitivity to FINO2 in Example 1; Figure 7 Schematic diagram C of the experimental results of the effect of endoperoxide on Gln sufficiency-mediated DNA sensitivity independent of ACSL4 in Example 1; Figure 8 Schematic diagram D of the experimental results of the effect of endoperoxide on ACSL4-independent Gln deprivation-mediated resistance to classical ferroptosis inducers in Example 1; Fig. 9 Schematic diagram E of the experimental results of the effect of endoperoxide on ACSL4-independent Gln deprivation-mediated FINO2 sensitivity in Example 1; Fig.10 Schematic diagram F of the experimental results of the effect of endoperoxide on Gln deprivation-mediated DHA sensitivity independent of ACSL4 in Example 1; Fig.11 Schematic diagram A of the experimental results of endoperoxide-induced ferroptosis in ACSL- / -MEF cells via iron oxidation in Example 1; Fig.12 Schematic diagram B of the experimental results of Example 1 in which endoperoxides induce ferroptosis in ACSL- / -MEF cells through iron oxidation; Fig.13 Schematic diagram C of the experimental results of Example 1 in which endoperoxides induce ferroptosis in ACSL- / -MEF cells via iron oxidation; Fig.14 Schematic diagram D of the experimental results of endoperoxide-induced ferroptosis in ACSL- / -MEF cells via iron oxidation in Example 1; Fig.15 Schematic diagram E of the experimental results of Example 1 in which endoperoxides induce ferroptosis in ACSL- / -MEF cells via iron oxidation; Fig.16 This is a schematic diagram of the experimental results of Gln deprivation promoting the EMT process of TNBC cells in Example 1; Fig.17 This is a schematic diagram of the results of the cell migration experiment in which Gln induces ferroptosis-resistant EMT in TNBC cells in Example 1; Fig.18 A is a schematic diagram of the experimental results of the potential mechanism of Gln deprivation on TNBC cell metastasis in Example 1; Fig.19 Schematic diagram B of the experimental results of the potential mechanism of Gln deprivation on TNBC cell metastasis in Example 1; Fig. 20 The figure is a schematic diagram of the experimental results of the in vivo experiment in Example 1 to detect the effects of ART combined with Gln deprivation and mTORC1 inhibitor on TNBC metastasis, A is a schematic diagram of the experimental results of mice, B is a comparison of the results of the control group, the mTORC1 inhibitor group alone, the ATS group alone, and the ATS combined with mTORC1 inhibitor group, and C is a schematic diagram of the results of tumor cell metastasis under the action of DHA combined with mTORC1 inhibitor. DETAILED DESCRIPTION

[0021] The present invention will be described in detail below with reference to the accompanying drawings and in combination with embodiments. The principles and features of the present invention are described below in combination with the accompanying drawings. It should be noted that the embodiments in this application and the features in the embodiments can be combined with each other without conflict. The embodiments are only used to explain the present invention and are not used to limit the scope of the present invention.

[0022] Unless otherwise specified, all reagents used in this manual are commercially available products.

[0023] This invention focuses on Gln deprivation inducing EMT resistant to classical ferroptosis inducers in TNBC, and mainly studies the mechanism of 1,2,4-trioxane endoperoxides, especially ART and FINO2, which induce ferroptosis insensitive to lipid metabolism and effectively inhibit TNBC metastasis. The mechanism of Gln deprivation mediating tumor cell metastasis and tolerance to classical ferroptosis inducers was found and verified by methods such as protein immunoblotting and CCK-8; technical studies such as animal metastasis models, lentiviral transfection and drug intervention confirmed that endoperoxides may become an effective treatment for TNBC cells to resist oxidative stress in the blood and metastasize to the blood.

[0024] The research contents of the present invention include the following four aspects: (1) Study the effect of Gln deprivation on the EMT process and ferroptosis sensitivity of TNBC Based on the fact that Gln can regulate lipid peroxidation accumulation and EMT in tumor cells, we first confirmed the effect of Gln deprivation on EMT, metastatic ability and ferroptosis sensitivity of breast cancer cells, and clarified that Gln deprivation can induce EMT in TNBC cells that is resistant to classical ferroptosis inducers. By comparing the differences in drug sensitivity of Gln-deprived cells to classical ferroptosis inducers (Rsl3 and Erastin) and endoperoxides (FINO2 and ART) and the EMT mediated by them, we clarified that endoperoxides can inhibit EMT resistant to classical ferroptosis inducers caused by Gln deprivation.

[0025] (2) Study the changes in lipid metabolism caused by Gln deprivation Wnt-β-catenin-GS-Gln in liver cancer promotes cell metabolism, proliferation and survival by phosphorylating mTORC1. The relationship between mTORC1 and lipid metabolism is relatively complex. It can inhibit lipid peroxidation through SREBP1 / SCD1-mediated MUFA synthesis, promote lipid peroxidation accumulation by affecting the content of GSH, and promote cell metastasis through S6K1 / 4E-BP1. Verification of mTORC1-mediated MUFA is the key to Gln deprivation leading to tumor cells' resistance to classical ferroptosis inducers by activating GS activity. Further study of Gln deprivation mediates EMT in breast cancer cells through phosphorylation of mTORC1 substrates S6K1 and 4E-BP1. It is clear that mTORC1 is a key node for lipid metabolism reprogramming caused by Gln deprivation and mediates EMT and resistance to classical ferroptosis inducers in breast cancer.

[0026] (3) Study the mechanism and characteristics of endoperoxide-induced ferroptosis ACSL4-mediated lipid metabolism is particularly critical in Rsl3-induced ferroptosis, while endoperoxides can directly oxidize PUFA-PLs. Therefore, we first confirmed that endoperoxide-induced ferroptosis is independent of ACSL4. By comparing the expression of ACSL4 under different Gln supply conditions, we clarified that Gln deprivation-induced TNBC cells to develop tolerance to classic ferroptosis inducers is independent of ACSL4, and whether Gln deprivation-mediated EMT is significantly related to ACSL4. Finally, we confirmed that endoperoxides can induce ferroptosis independent of ACSL4 and promote the killing of Gln deprivation-induced EMT cells.

[0027] (4) Study the effects of endoperoxides, especially ART, on TNBC metastasis and its mechanism Given that the mechanism of action of ART may be similar to that of FINO2, it is clear that ART can effectively interfere with Gln deprivation-mediated TNBC cell resistance to classical ferroptosis inducers and block Gln deprivation-mediated TNBC cell metastasis, and this process is also independent of ACSL4. In addition, since ART can regulate tumor progression by inhibiting mTORC1, the present invention will study whether ART can change mTORC1-mediated lipid metabolic reprogramming. The in situ mouse breast cancer lung metastasis model was used to verify whether endoperoxides represented by ART can effectively interfere with the in vivo metastasis of tumor cells, and to study their mechanism of action. The technical approach adopted by the present invention, see Figure 1 .

[0028] Example 1 This embodiment is an application of endoperoxide combined with glutamine deprivation in a tumor cell metastasis inhibitory drug whose ferroptosis sensitivity is not dependent on ACSL4. Taking triple-negative breast cancer (TNBC) as an example, TNBC is a special type of breast cancer characterized by negative estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). This type of breast cancer accounts for about 10% to 20% of all breast cancer cases. Due to the lack of these receptors, triple-negative breast cancer is ineffective for hormone therapy and HER2 targeted therapy, and the treatment options are relatively limited. The incidence of triple-negative breast cancer is higher in young women, and it has a higher risk of invasiveness and recurrence. In addition, the prognosis of triple-negative breast cancer is relatively poor because it grows fast and is easy to metastasize.

[0029] TNBC is ineffective for hormone therapy and HER2 targeted therapy, and treatment options are relatively limited. In addition, TNBC has a relatively poor prognosis due to its rapid growth rate and easy cell metastasis, and existing technologies make it difficult to effectively inhibit the metastasis of TNBC cells.

[0030] In this example, a new EMT phenomenon with ferroptosis tolerance characteristics was found in TNBC, which is inconsistent with the current conclusion that EMT cells are more sensitive to ferroptosis. The research process of this example shows that this ferroptosis tolerance is more conducive to EMT cells to withstand the oxidative stress environment in the blood after entering the bloodstream, thereby more effectively transferring. Therefore, the present invention reveals that ferroptosis tolerance is a key feature of TNBC's strong metastatic ability.

[0031] Long-chain acyl-CoA synthetase 4 (ACSL4), as a key component of membrane lipids, is a key enzyme in the synthesis and transformation of polyunsaturated fatty acids (PUFAs). It can induce cells to be sensitive to ferroptosis and increase the fluidity of cell membranes.

[0032] Given that the rapid development of TNBC is more dependent on Gln, this example simulates the condition of severe consumption of Gln during the development of TNBC by removing Gln from the cell culture medium as the Gln-experimental group, and Gln is added to the culture medium as the Gln+experimental group.

[0033] See also Figure 2 , showing the EMT of 4T1 cells and HCC1973 cells resistant to ferroptosis induced by the inducer Erastin under Gln+ and Gln- conditions, and the EMT of MDA-MB-231 cells resistant to ferroptosis induced by the inducer Rsl3 under Gln+ and Gln- conditions, both showing that the cells in the Gln- group were more sensitive to ferroptosis induced by the inducer and EMT. Figure 3, Gln-deprivation-induced TNBC cells remain sensitive to FINO2-induced ferroptosis.

[0034] This example compares the expression of ACSL4 under different Gln supply conditions to clarify that Gln deprivation-induced TNBC cell tolerance to classical ferroptosis inducers is independent of ACSL4, and whether Gln deprivation-mediated EMT is significantly related to ACSL4. Specifically, 1) protein immunoblotting was used to detect ACSL4 protein expression in Gln+ and Gln- group cells; 2) CCK-8 was used to detect the sensitivity of Gln-deprived cells with knockdown or inhibition of ACSL4 to ferroptosis inducers Rsl3, Erastin, FINO2, MLH, TBH, ART and DHA; 3) after treatment with low concentrations of endoperoxides, the metastatic ability of cells with Gln deprivation accompanied by knockdown or inhibition of ACSL4 was detected. See Figure 4 By detecting the characteristics of endoperoxide-induced ferroptosis in TNBC cells, we found that ACSL4 was lowly expressed in Gln-deprived TNBC cells, ultimately confirming that endoperoxide can induce ferroptosis independent of ACSL4.

[0035] Given that the ACSL4-mediated lipid oxidation pathway is considered to be an important process for the production of lipid peroxides in ferroptosis caused by Rsl3-induced loss of reducing ability, this example also detected the role of ACSL4 in ferroptosis induced by Rsl3, FINO2, and DHA, respectively, and found that knocking down ACSL4 had a greater effect on the classic ferroptosis inducer Rsl3, see Figure 5 ; but it does not affect the cytotoxicity produced by FINO2 and DHA, see Figure 6 and Figure 7 Furthermore, knockdown of ACSL4 in Gln-deprived cells induced mild resistance to Rsl3-induced ferroptosis, but had no effect on FINO2- and DHA-mediated ferroptosis sensitivity, see Figure 8-Figure 10 These results suggest that, since endoperoxide-mediated ferroptosis sensitivity is independent of ACSL4, it could be used to treat cells that are resistant to classical ferroptosis inducers induced by Gln deprivation.

[0036] Furthermore, in this example, endoperoxides induce ferroptosis in TNBC cells by oxidizing iron.

[0037] See also Figure 11-Figure 15 Oxidative inducers such as FINO2, TBH, and MLH can induce ferroptosis in cells through iron oxidation rather than other forms of cell death, and this process is independent of ACSL4.

[0038] Furthermore, in this embodiment, endoperoxide inhibits epithelial-mesenchymal transition (EMT) of TNBC, wherein the epithelial-mesenchymal transition of TNBC is inhibited by regulating the mTORC1 signaling pathway, and the regulation of the mTORC1 signaling pathway is to upregulate the expression of the mTORC1 protein.

[0039] Based on the fact that Gln can regulate lipid peroxidation accumulation and EMT in tumor cells, we first confirmed the effect of Gln deprivation on EMT, metastatic ability and ferroptosis sensitivity of breast cancer cells, and clarified that Gln deprivation can induce EMT in TNBC cells that is resistant to classical ferroptosis inducers. By comparing the differences in drug sensitivity of Gln-deprived cells to classical ferroptosis inducers (Rsl3 and Erastin) and endoperoxides (FINO2 and ART) and the EMT mediated by them, we clarified that endoperoxides can inhibit EMT resistant to classical ferroptosis inducers caused by Gln deprivation.

[0040] To examine the mechanism of lipid metabolism changes in Gln deprivation regulating tumor cell metastasis and ferroptosis resistance, we used the following methods: 1) Western blotting was used to detect the GS and mTORC1 protein levels and upstream and downstream relationships in Gln+ and Gln- group cells; 2) Rapamycin (Rapa) was used to inhibit the mTORC1 signaling pathway, and the metastatic ability of Gln- group breast cancer cells and their sensitivity to ferroptosis inducers Rsl3, Erastin, FINO2, MLH, TBH, ART and DHA were detected; the effect of rapamycin on Rsl3-induced ferroptosis after supplementation with MUFA palmitoleic acid (16:1, PO) or oleic acid (18:1, OA) was detected; 3) After drugs inhibited the phosphorylation of S6K1 and 4E-BP1, the E-cad / Snail protein expression and cell metastatic ability of Gln-deprived breast cancer cells were detected.

[0041] See also Fig.16 , showing that Gln deprivation promotes the EMT process. The results show the phenomenon of induced EMT in 4T1 cells and MDA-MB-231 cells under Gln+ and Gln- conditions. The EMT marker E-cad was significantly reduced in the Gln-group of the two cell groups, and the EMT marker Snail was expressed as an increase in the Gln-group of the two cell groups. It can be seen that Gln deprivation can promote EMT of tumor cells tolerant to classic ferroptosis inducers, and this ferroptosis tolerance may be more conducive to EMT cells to withstand the oxidative stress environment in the blood after entering the bloodstream, thereby causing more effective metastasis. Different from the metastatic EMT cancer cells believed in the prior art, they also become more sensitive to the ferroptosis pathway.

[0042] See also Fig.17The migration experiment results showed that the number of cells in the Gln-group without Lip-1 increased significantly, indicating that the number of migrating cells increased, that is, glutamine deprivation induced EMT in TNBC.

[0043] To explore the possible mechanism by which Gln deprivation promotes breast cancer metastasis, this example also detected the expression of GS and mTORC1 proteins after Gln deprivation, as well as the effect of the mTORC1 inhibitor Rapa on the EMT expression of breast cancer cells, see Fig.18 , showing that Gln deprivation can activate GS activity and is accompanied by upregulation of mTORC1 expression, see Fig.19 , indicating that the mTORC1 signaling pathway can regulate EMT. The above results indicate that Gln deprivation may regulate breast cancer cell metastasis and resistance to classic ferroptosis inducers through changes in lipid metabolism mediated by mTORC1.

[0044] In this embodiment, see Fig. 20 In vivo experiments were performed to detect the effect of ART on TNBC metastasis under Gln deprivation. The luciferase-labeled Control group, Rapamycin group (mTORC1 inhibitor group alone), ATS group (endoperoxide group alone), and ATS+ Rapamycin group (endoperoxide and mTORC1 inhibitor group were applied simultaneously) were used. 5 mg / kg of drug was injected intraperitoneally once a day for treatment. The metastasis of breast tumors to the lungs in vivo was observed by in vivo animal fluorescence imaging technology, and the size and number of tumor nodules metastasized to the lungs in the three groups were observed after dissection. In this example, given that the ART derivative ATS has better stability and the two have similar therapeutic effects in tumors, the in vivo experiment of ART drug treatment uses the ART derivative ATS as a therapeutic drug. See. Fig. 20 The results showed that under Gln deprivation, the tumor signal of mice injected with ATS alone and mTORC1 inhibitor alone was significantly lower than that of the control group mice not injected with any drugs; the number of lung metastatic nodules was significantly less; while the mice injected with ATS and mTORC1 inhibitor drugs at the same time showed the lowest tumor signal and the least number of lung metastatic nodules.

[0045] It can be seen that endoperoxides represented by ART and FINO2 combined with Gln deprivation and mTORC1 inhibitors are expected to be developed into effective drugs for the treatment of tumor cell metastasis.

[0046] Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the scope of protection of the invention.

Claims

1. The use of endoperoxide combined with glutamine deprivation in a tumor cell metastasis inhibitory drug whose ferroptosis sensitivity is independent of ACSL4, characterized in that: The glutamine deprivation includes blocking glutamine supply and / or synthesis.

2. The use according to claim 1, characterized in that: Also included is an mTORC1 inhibitor, wherein the endoperoxide is combined with glutamine deprivation and the mTORC1 inhibitor to inhibit the epithelial-mesenchymal transition of tumor cells.

3. The use according to claim 2, characterized in that: Inhibit the epithelial-mesenchymal transition of tumor cells by regulating the mTORC1 signaling pathway.

4. The use according to claim 3, characterized in that: The regulation of the mTORC1 signaling pathway is to upregulate the expression of the mTORC1 protein.

5. The use according to any one of claims 1 to 4, characterized in that: The endoperoxide is a 1,2,4-trioxane endoperoxide.

6. The use according to claim 5, characterized in that: The 1,2,4-trioxane endoperoxide is artemisinin or FINO2.

7. The use according to claim 6, characterized in that: The tumors include triple-negative breast tumors.

8. The use according to claim 7, characterized in that: The tumor cell metastasis inhibitory drug contains an effective amount of artemisinin and / or FINO2 that inhibits the epithelial-mesenchymal transition of tumor cells.

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