Use of duloxetine and chemotherapeutic drug in preparation of pharmaceutical composition for treating or preventing cancer

Abstract

A use of duloxetine and a chemotherapeutic drug in the preparation of a pharmaceutical composition for treating or preventing cancer, comprising administering an effective amount of duloxetine and a chemotherapeutic drug to an individual in need, which achieves a better effect compared to administration of duloxetine or the chemotherapeutic drug alone.

Description

Use of duloxetine and chemotherapeutic agents for the preparation of a pharmaceutical composition for treating or preventing cancer TECHNICAL FIELD

[0001] The present disclosure relates to a use of preparing a pharmaceutical composition for treating or preventing cancer, in particular, to a use of duloxetine and chemotherapeutic agents for the preparation of a pharmaceutical composition for treating or preventing cancer. BACKGROUND

[0002] Cancer has long been the leading cause of death worldwide, and the number of people suffering from cancer is rising year by year, so treating cancer is an important issue. Cancer treatment can be divided into surgical treatment, radiation therapy, chemotherapy, and targeted therapy. Cancer cells are characterized by uncontrolled cell proliferation and the potential to invade or metastasize to distant tissues. Clinical manifestations of cancer include weight loss, muscle atrophy, decreased mobility, fatigue, anorexia, satiety, lethargy, pallor, anemia, emaciation, electrolyte imbalance, decreased protein and lipid synthesis, and blood sugar instability. When a patient loses more than 5% of their body weight in 6 months and has the above symptoms, it is called "cachexia", and in severe cases it is commonly known as "skin and bones".

[0003] Despite the progress in cancer treatment over the past few decades, such as surgery, radiotherapy, chemotherapy, and immunotherapy, these treatment methods still have significant side effects. For example, some patients cannot undergo surgical resection of tumors due to their own relationship, or surgery may not completely remove tumor tissue. Furthermore, most existing anticancer agents cannot effectively distinguish between cancer cells and normal cells, so these chemotherapy-related side effects or systemic toxicity caused by individual chemotherapy limit the therapeutic effect of chemotherapy. In addition, as with the aforementioned chemotherapy, radiotherapy can also damage normal tissues, thus limiting its effectiveness. In immunotherapy, cancer cells have developed mechanisms to evade immune responses, so the effectiveness of immunotherapy for cancer patients is sometimes not significant.

[0004] Therefore, there is an unmet need in the art for developing therapies for treating and inhibiting cancer, and there is an urgent need in the art to develop a method for treating cancer to solve the above problems in the art and meet the clinical needs.

[0005] SUMMARY

[0006] Use of duloxetine and chemotherapeutic agents for the preparation of a pharmaceutical composition for treating or preventing cancer.

[0007] A method for treating or preventing cancer, comprising administering to a subject in need thereof an effective amount of duloxetine and a chemotherapeutic agent.

[0008] A pharmaceutical composition for treating or preventing cancer, comprising an effective amount of duloxetine and a chemotherapeutic agent.

[0009] BRIEF DESCRIPTION OF DRAWINGS

[0010] The present disclosure will be more readily understood by reference to the following description, taken in conjunction with the accompanying drawings.

[0011] Figure 1 shows the effect of duloxetine and docetaxel on triple negative breast cancer (MDA-MB-231 cell line). G1 : IC50 of docetaxel (0.004 μM); G2: ½ IC50 of docetaxel (0.002 μM); G3: duloxetine (5 μM); G4: duloxetine (5 μM) + ½ IC50 of docetaxel (0.002 μM); G5: duloxetine (5 μM) + IC50 of docetaxel (0.004 μM). 50 (0.004 μM) ; G2: ½ IC50 of docetaxel (0.002 μM); G3: duloxetine (5 μM); G4: duloxetine (5 μM) + ½ IC50 of docetaxel (0.002 μM); G5: duloxetine (5 μM) + IC50 of docetaxel (0.004 μM). 50 (0.002 μM); G3: duloxetine (5 μM); G4: duloxetine (5 μM) + ½ IC50 of docetaxel (0.002 μM); G5: duloxetine (5 μM) + IC50 of docetaxel (0.004 μM). 50 (0.002 μM); G3: duloxetine (5 μM); G4: duloxetine (5 μM) + ½ IC50 of docetaxel (0.002 μM); G5: duloxetine (5 μM) + IC50 of docetaxel (0.004 μM). 50 (0.004 μM) ; G2: ½ IC50 of docetaxel (0.002 μM); G3: duloxetine (5 μM); G4: duloxetine (5 μM) + ½ IC50 of docetaxel (0.002 μM); G5: duloxetine (5 μM) + IC50 of docetaxel (0.004 μM).

[0012] Figure 2 shows the effect of duloxetine and cisplatin on triple negative breast cancer (MDA-MB-231 cell line). G1 : IC50 of cisplatin (3 μM); G2: ½ IC50 of cisplatin (1.5 μM); G3: duloxetine (5 μM); G4: duloxetine (5 μM) + ½ IC50 of cisplatin (1.5 μM); G5: duloxetine (5 μM) + IC50 of cisplatin (3 μM). 50 (3 μM); G2: ½ IC50 of cisplatin (1.5 μM); G3: duloxetine (5 μM); G4: duloxetine (5 μM) + ½ IC50 of cisplatin (1.5 μM); G5: duloxetine (5 μM) + IC50 of cisplatin (3 μM). 50 (1.5 μM); G3: duloxetine (5 μM); G4: duloxetine (5 μM) + ½ IC50 of cisplatin (1.5 μM); G5: duloxetine (5 μM) + IC50 of cisplatin (3 μM). 50 (1.5 μM).

[0013] Figure 3 shows the effect of duloxetine and cyclophosphamide on triple negative breast cancer (MDA-MB-231 cell line). G1 : IC50 of cyclophosphamide (40 μM); G2: ½ IC50 of cyclophosphamide (20 μM); G3: duloxetine (5 μM); G4: duloxetine (5 μM) + ½ IC50 of cyclophosphamide (20 μM); G5: duloxetine (5 μM) + IC50 of cyclophosphamide (40 μM). 50 (40 μM); G2: ½ IC50 of cyclophosphamide (20 μM); G3: duloxetine (5 μM); G4: duloxetine (5 μM) + ½ IC50 of cyclophosphamide (20 μM); G5: duloxetine (5 μM) + IC50 of cyclophosphamide (40 μM). 50 (20 μM); G3: duloxetine (5 μM); G4: duloxetine (5 μM) + ½ IC50 of cyclophosphamide (20 μM); G5: duloxetine (5 μM) + IC50 of cyclophosphamide (40 μM). 50 (20 μM); G3: duloxetine (5 μM); G4: duloxetine (5 μM) + ½ IC50 of cyclophosphamide (20 μM); G5: duloxetine (5 μM) + IC50 of cyclophosphamide (40 μM). 50 (40 μM).

[0014] Figure 4 shows the effect of duloxetine and 5-fluorouracil on triple negative breast cancer (MDA-MB-231 cell line). G1 : IC50 of 5-fluorouracil (400 μM); G2: ½ IC50 of 5-fluorouracil (200 μM); G3: duloxetine (5 μM); G4: duloxetine (5 μM) + ½ IC50 of 5-fluorouracil (200 μM); G5: duloxetine (5 μM) + IC50 of 5-fluorouracil (400 μM). 50 (400 μM); G2: ½ IC50 of 5-fluorouracil (200 μM); G3: duloxetine (5 μM); G4: duloxetine (5 μM) + ½ IC50 of 5-fluorouracil (200 μM); G5: duloxetine (5 μM) + IC50 of 5-fluorouracil (400 μM). 50G3: Duloxetine (5 μΜ); G4: Duloxetine (5 μΜ) + 5-fluorouracil IC 50 G5: Duloxetine (5 μΜ) + 5-fluorouracil IC 50 (400 μΜ).

[0015] Figure 5 shows the effect of duloxetine and doxorubicin on triple negative breast cancer (MDA-MB-231 cell line). G1 : IC of doxorubicin 50 (0.5 μΜ); G2: ½ IC of doxorubicin 50 (0.25 μΜ); G3: Duloxetine (5 μΜ); G4: Duloxetine (5 μΜ) + ½ IC of doxorubicin 50 (0.25 μΜ); G5: Duloxetine (5 μΜ) + IC of doxorubicin 50 (0.5 μΜ).

[0016] Figure 6 shows the effect of duloxetine and temozolomide on triple negative breast cancer (MDA-MB-231 cell line). G1 : IC of temozolomide 50 (400 μΜ); G2: ½ IC of temozolomide 50 (200 μΜ); G3: Duloxetine (5 μΜ); G4: Duloxetine (5 μΜ) + ½ IC of temozolomide 50 (400 μΜ); G5: Duloxetine (5 μΜ) + IC of temozolomide 50 (200 μΜ).

[0017] Figure 7 shows the effect of duloxetine and osimertinib (AZD-9291) on triple negative breast cancer (MDA-MB-231 cell line). G1 : IC of osimertinib 50 (5 μΜ); G2: ½ IC of osimertinib 50 (2.5 μΜ); G3: Duloxetine (5 μΜ); G4: Duloxetine (5 μΜ) + ½ IC of osimertinib 50 (2.5 μΜ); G5: Duloxetine (5 μΜ) + IC of osimertinib 50 (5 μΜ).

[0018] Figure 8 shows the effect of duloxetine and etoposide on triple negative breast cancer (MDA-MB-231 cell line). G1 : IC of etoposide 50 (100 μΜ); G2: ½ IC of etoposide 50(50 μM); G3: Duloxetine (5 μM); G4: Duloxetine (5 μM) + 1 / 2 IC50 of etoposide 50 (50 μM); G5: IC50 of duloxetine (5 μM) + etoposide 50 (100μM).

[0019] Figure 9 shows the effects of duloxetine and docetaxel on non-small cell lung cancer (A549 cell line). G1: IC50 of docetaxel 50 (0.004 μM); G2: 1 / 2 IC50 of docetaxel 50 (0.002 μM); G3: Duloxetine (5 μM); G4: Duloxetine (5 μM) + Docetaxel 1 / 2 IC 50 (0.002 μM); G5: IC50 of duloxetine (5 μM) + docetaxel 50 (0.004μM).

[0020] Figure 10 shows the effects of duloxetine and 5-fluorouracil on non-small cell lung cancer (A549 cell line). G1: IC50 of 5-fluorouracil 50 (400 μM); G2: 1 / 2 IC50 of 5-fluorouracil 50 (200μM);

[0021] G3: Duloxetine (5 μM); G4: Duloxetine (5 μM) + 1 / 2 IC50 of 5-fluorouracil 50 (200 μM); G5: IC50 of duloxetine (5 μM) + 5-fluorouracil 50 (400μM).

[0022] Figure 11 shows the effects of duloxetine and doxorubicin on non-small cell lung cancer (A549 cell line). G1: IC50 of doxorubicin 50 (0.5 μM); G2: 1 / 2 IC50 of doxorubicin 50 (0.25 μM); G3: Duloxetine (5 μM); G4: Duloxetine (5 μM) + Doxorubicin 1 / 2 IC 50 (0.25 μM); G5: IC50 of duloxetine (5 μM) + doxorubicin 50 (0.5μM).

[0023] Figure 12 shows the effects of duloxetine and temozolomide on non-small cell lung cancer (A549 cell line). G1: IC50 of temozolomide. 50 (400 μM); G2: 1 / 2 IC50 of temozolomide 50 (200 μM); G3: Duloxetine (5 μM); G4: Duloxetine (5 μM) + Temozolomide 1 / 2 IC 50(400 mM); G5: Duloxetine (5 mM) + IC of Temozolomide 50 (200 mM).

[0024] Figure 13 shows the effect of Duloxetine and Osimertinib (AZD-9291) on non-small cell lung cancer (A549 cell line). G1 : IC of Osimertinib 50 (5 mM); G2: ½ IC of Osimertinib 50 (2.5 mM); G3: Duloxetine (5 mM); G4: Duloxetine (5 mM) + ½ IC of Osimertinib 50 (2.5 mM); G5: Duloxetine (5 mM) + IC of Osimertinib 50 (5 mM).

[0025] Figure 14 shows the effect of Duloxetine and Sorafenib on non-small cell lung cancer (A549 cell line). G1 : IC of Sorafenib 50 (20 mM); G2: ½ IC of Sorafenib 50 (10 mM); G3: Duloxetine (5 mM); G4: Duloxetine (5 mM) + ½ IC of Sorafenib 50 (10 mM); G5: Duloxetine (5 mM) + IC of Sorafenib 50 (20 mM).

[0026] Figure 15 shows the effect of Duloxetine and Etoposide on non-small cell lung cancer (A549 cell line). G1 : IC of Etoposide 50 (100 mM); G2: ½ IC of Etoposide 50 (50 mM); G3: Duloxetine (5 mM); G4: Duloxetine (5 mM) + ½ IC of Etoposide 50 (50 mM); G5: Duloxetine (5 mM) + IC of Etoposide 50 (100 mM).

[0027] Figure 16 shows the effect of Duloxetine and Cisplatin on pancreatic cancer (Mia-PaCa2 cell line). G1 : IC of Cisplatin 50 (3 mM); G2: ½ IC of Cisplatin 50 (1.5 mM); G3: Duloxetine (5 mM); G4: Duloxetine (5 mM) + ½ IC of Cisplatin 50 (3 mM); G5: Duloxetine (5 mM) + IC of Cisplatin 50 (1.5 mM).

[0028] Figure 17 shows the effect of duloxetine and doxorubicin on pancreatic cancer (Mia-PaCa2 cell line). G1 : IC of doxorubicin 50 G2: ½ IC of doxorubicin 50 G3: duloxetine (5 μΜ) 50 G4: duloxetine (5 μΜ) + ½ IC of doxorubicin 50 G5: duloxetine (5 μΜ) + IC of doxorubicin

[0029] Figure 18 shows the effect of duloxetine and osimertinib (AZD-9291 ) on pancreatic cancer (Mia-PaCa2 cell line). G1 : IC of osimertinib 50 G2: ½ IC of osimertinib 50 G3: duloxetine (5 μΜ)

[0030] G4: duloxetine (5 μΜ) + ½ IC of osimertinib 50 G5: duloxetine (5 μΜ) + IC of osimertinib 50 G6: duloxetine (5 μΜ)

[0031] Figure 19 shows the effect of duloxetine and etoposide on pancreatic cancer (Mia-PaCa2 cell line). G1 : IC of etoposide 50 G2: ½ IC of etoposide 50 G3: duloxetine (5 μΜ) 50 G4: duloxetine (5 μΜ) + ½ IC of etoposide 50 G5: duloxetine (5 μΜ) + IC of etoposide

[0032] Figure 20 shows the effect of duloxetine and docetaxel on liver cancer (PLC / PRF / 5 cell line). G1 : IC of docetaxel 50 G2: ½ IC of docetaxel 50 G3: duloxetine (5 μΜ) 50 G4: duloxetine (5 μΜ) + ½ IC of docetaxel 50 G5: duloxetine (5 μΜ) + IC of docetaxel

[0033] Figure 21 shows the effect of duloxetine and cisplatin on liver cancer (PLC / PRF / 5 cell line). G1 : IC of cisplatin 50(3 μM); G2: 1 / 2 IC of cisplatin 50 (1.5 μM); G3: duloxetine (5 μM); G4: duloxetine (5 μM) + 1 / 2 IC of cisplatin 50 (1.5 μM); G5: duloxetine (5 μM) + IC of cisplatin 50 (1.5 μM).

[0034] Figure 22 shows the effect of duloxetine and 5-fluorouracil on liver cancer (PLC / PRF / 5 cell line). G1 : IC of 5-fluorouracil 50 (400 μM); G2: 1 / 2 IC of 5-fluorouracil 50 (200 μM); G3: duloxetine (5 μM); G4: duloxetine (5 μM) + 1 / 2 IC of 5-fluorouracil 50 (200 μM); G5: duloxetine (5 μM) + IC of 5-fluorouracil 50 (400 μM).

[0035] Figure 23 shows the effect of duloxetine and doxorubicin on liver cancer (PLC / PRF / 5 cell line). G1 : IC of doxorubicin 50 (0.5 μM); G2: 1 / 2 IC of doxorubicin 50 (0.25 μM); G3: duloxetine (5 μM); G4: duloxetine (5 μM) + 1 / 2 IC of doxorubicin 50 (0.25 μM); G5: duloxetine (5 μM) + IC of doxorubicin 50 (0.5 μM).

[0036] Figure 24 shows the effect of duloxetine and sorafenib on liver cancer (PLC / PRF / 5 cell line). G1 : IC of sorafenib 50 (20 μM); G2: 1 / 2 IC of sorafenib 50 (10 μM); G3: duloxetine (5 μM); G4: duloxetine (5 μM) + 1 / 2 IC of sorafenib 50 (10 μM); G5: duloxetine (5 μM) + IC of sorafenib 50 (20 μM).

[0037] Figure 25 shows the effect of duloxetine and etoposide on liver cancer (PLC / PRF / 5 cell line). G1 : IC of etoposide 50 (100 μM); G2: 1 / 2 IC of etoposide 50 (50 μM); G3: duloxetine (5 μM); G4: duloxetine (5 μM) + 1 / 2 IC of etoposide 50(50 μM); G5: duloxetine (5 μM) + IC of etoposide 50 (100 μM).

[0038] Figure 26 shows the effect of duloxetine and docetaxel on glioblastoma (LN-229 cell line). Gl: IC of docetaxel 50 (0.004 μM); G2: ½ IC of docetaxel 50 (0.002 μM); G3: duloxetine (5 μM); G4: duloxetine (5 μM) + ½ IC of docetaxel 50 (0.002 μM); G5: duloxetine (5 μM) + IC of docetaxel 50 (0.004 μM).

[0039] Figure 27 shows the effect of duloxetine and cyclophosphamide on glioblastoma (LN-229 cell line). Gl: IC of cyclophosphamide 50 (40 μM); G2: ½ IC of cyclophosphamide 50 (20 μM); G3: duloxetine (5 μM); G4: duloxetine (5 μM) + ½ IC of cyclophosphamide 50 (20 μM); G5: duloxetine (5 μM) + IC of cyclophosphamide 50 (40 μM).

[0040] Figure 28 shows the effect of duloxetine and 5-fluorouracil on glioblastoma (LN-229 cell line). Gl: IC of 5-fluorouracil 50 (400 μM); G2: ½ IC of 5-fluorouracil 50 (200 μM); G3: duloxetine (5 μM); G4: duloxetine (5 μM) + ½ IC of 5-fluorouracil 50 (200 μM); G5: duloxetine (5 μM) + IC of 5-fluorouracil 50 (400 μM).

[0041] Figure 29 shows the effect of duloxetine and temozolomide on glioblastoma (LN-229 cell line). Gl: IC of temozolomide 50 (400 μM); G2: ½ IC of temozolomide 50 (200 μM); G3: duloxetine (5 μM); G4: duloxetine (5 μM) + ½ IC of temozolomide 50 (400 μM); G5: duloxetine (5 μM) + IC of temozolomide 50 (200 μM).

[0042] Figure 30 shows the effect of duloxetine and osimertinib (AZD-9291) on glioblastoma (LN-229 cell line). G1 : IC of osimertinib 50 G2: ½ IC of osimertinib 50 G3: duloxetine (5 μΜ) 50 G4: duloxetine (5 μΜ) + ½ IC of osimertinib 50 G5: duloxetine (5 μΜ) + IC of osimertinib

[0043] Figure 31 shows the effect of duloxetine and etoposide on hepatocarcinoma (PLC / PRF / 5 cell line). G1 : IC of etoposide 50 G2: ½ IC of etoposide 50 G3: duloxetine (5 μΜ) 50 G4: duloxetine (5 μΜ) + ½ IC of etoposide 50 G5: duloxetine (5 μΜ) + IC of etoposide

[0044] Figure 32 shows the tumor shrinkage of the individuals of the duloxetine + neoadjuvant chemotherapy (NACT) group after 24 weeks of treatment. R001, R002, R003, R004, R005, R006 and R008 represent the tumor shrinkage of 7 subjects, respectively, and 22.65% represents the average tumor shrinkage. R002, R004 and R008 are CR, so they are collinear.

[0045] Figure 33 shows the tumor shrinkage of the NACT group and the duloxetine + NACT group. ***: P < 0.001.

[0046] Figure 34 shows the waterfall plot of the tumor shrinkage of the NACT group and the duloxetine + NACT group.

[0047] Figure 35 shows the changes in the computed tomography of the tumor of the individuals of the duloxetine + NACT group before (left half) / after (right half) treatment, for the complete response (CR) and for the partial response (PR).

[0048] Figure 36 shows the objective response rates (ORR) of the combined standard treatment.

[0049] Figure 37 shows Foxp3 expression in peripheral blood mononuclear cells (upper panel) and regression analysis of Foxp3-V1 versus tumor shrinkage (lower panel) in the Duloxetine + NACT group before and after treatment. V1 : Visit 1, V8: Visit 8; V16: Visit 16; V18: Visit 18.

[0050] Figure 38 shows IDO-1 expression in peripheral blood mononuclear cells (upper panel) and regression analysis of IDO-1-V1 versus tumor shrinkage (lower panel) in the Duloxetine + NACT group before and after treatment. V1 : Visit 1, V8: Visit 8; V16: Visit 16; V18: Visit 18.

[0051] Figure 39 shows IGKC expression in peripheral blood mononuclear cells (upper panel) and regression analysis of IGKC-V18 versus tumor shrinkage (lower panel) in the Duloxetine + NACT group before and after treatment. V1 : Visit 1, V8: Visit 8; V16: Visit 16; V18: Visit 18. DETAILED DESCRIPTION

[0052] The following examples are provided to illustrate the present disclosure in detail. Those skilled in the art, after reading the disclosure provided herein, will readily understand the advantages and benefits of the present disclosure and will further recognize that changes and / or modifications can be suggested by the disclosure, and the inherent nature of the disclosure, without departing from the essential characteristics of the different aspects and applications thereof. Accordingly, it is intended that any element or method disclosed in any embodiment of the present disclosure can be combined with any other element or method disclosed in any other embodiment of the present disclosure.

[0053] The articles "a," "an," and "the" each refer to one or more (i.e., at least one) of the grammatical object of the article. The terms "or" and "and / or" are used herein interchangeably and are each to be interpreted as an inclusive-inclusive rather than an exclusive-inclusive. The term "includes" is used herein to mean, and is used interchangeably with, the phrase "includes but is not limited to." As used herein, the term "about" is used to allow for typical tolerances and variations in the art of the relevant field. For example, "about" can be understood to refer to a range of values that fall within typical tolerances for a given value. When "about" precedes a series of numbers or a range, it is to be understood that "about" can modify each of the numbers in that series or range. For example, numerical values are intended to encompass variations of ±20%, ±10%, ±5%, ±1%, ±0.5%, or ±0.1% from the stated value. As used herein, numerical ranges are inclusive and combinable, and any numerical value falling within the range recited is to be considered as if it were specifically written out in the range. For example, it is to be understood that a range such as "20 to 30%" includes any sub-range between the minimum value of 20% and the maximum value of 30%, such as a sub-range from 20% to 25%, from 25% to 30%, and from 22.5% to 27.5%. Such variations can occur, for example, due to experimental error, typical errors in measuring or handling a compound, composition, concentrate, or formulation, differences in the source, manufacture, or purity of a starting material or ingredient used in the present disclosure, or similar considerations.

[0054] As described herein, "individual" is used to refer to any vertebrate, including, but not limited to, a human or a mammal, such as a deer, a mule, an elk, a black-tailed deer. In some preferred embodiments, the individual is a mammal, such as a human or a non-human mammal, for example, a domesticated mammal, such as a dog, a cat, a horse, a rat, a mouse, and the like, or a livestock mammal, such as a cow, a sheep, a pig, a deer, and the like.

[0055] As described herein, the terms "comprise(s)," "include(s)," "having," "contains" "includes" and any other variation thereof are intended to cover non-exclusive inclusion. For example, a process, method, article, or apparatus that "comprises" a list of elements is not necessarily limited to only those elements but can include other elements not expressly listed or inherent to such process, method, article, or apparatus. Further, unless expressly stated to the contrary, where a process is described consisting of various elements and / or acts, the elements and / or acts can be carried out in any order, unless otherwise specifically necessary or implicit from the disclosure.

[0056] As described herein, the term "effective amount" refers to an amount of an active agent or a pharmaceutical composition sufficient to produce a prophylactic or therapeutic effect in an individual in need thereof. In some embodiments, an effective amount of the composition causes prevention or reduction of appearance and / or symptoms associated with an undesirable condition. The effective amount can be varied by one of ordinary skill in the art depending upon the use of the excipient, the route of administration, the possibility of co-usage with other therapeutic treatments, or the condition being treated, but the present disclosure is not limited thereto.

[0057] As described herein, the term "administering" refers to the introduction of an active ingredient into an individual by a method or route such that at least a portion of the active ingredient is positioned at a desired site to produce a desired effect. For example, the active ingredients of the present disclosure can be administered to an individual by means of injection or topical application, but the present disclosure is not so limited. Administration of the compositions of the present disclosure can be performed in the systemic or local environment of the individual. For example, the site of topical administration can be any site in the body where tissue development is desired or beneficial, such as: a joint, a surgical site, a segmental bone gap or site of non-union, a wound, an ulcer, or an inflammatory rash.

[0058] As described herein, the term "preventing" refers to prophylactic or preventative measures against a disease, symptom, or condition, such as, but not limited to, the application or administration of one or more active agents to an individual who is not yet diagnosed with the disease, symptom, or condition, but who is susceptible to, or otherwise at risk of, developing the disease, symptom, or condition.

[0059] As described herein, the term "treating" refers to obtaining a desired pharmacological or physiologic effect, such as, but not limited to, inhibiting the growth of cancer cells or reducing the size of a lesion tumor. The effect can be prophylactic in terms of completely or partially preventing a condition, symptom, disease, or disorder, and / or can be therapeutic in terms of a partial or complete cure for a condition, and / or adverse effect attributable to the condition or disease.

[0060] As described herein, the term "pharmaceutically acceptable carrier or excipient" refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulation material. In some embodiments, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a cosmetic or pharmaceutical formulation, and suitable for use in contact with the tissue or organ of an individual (e.g., a human or animal) without excessive toxicity, irritation, allergic response, immunogenicity, or other problem or complication, commensurate with a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 22ndEd.; Allen, Ed.; Philadelphia, PA, 2012; Handbook of Pharmaceutical Excipients, 7thEd.; Rowe et al., Eds.; Pharmaceutical Press and American Pharmaceutical Association: 2012; Handbook of Pharmaceutical Additives, 3rdEd.; Ash and Ash, Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2ndEd.; Gibson, Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0061] As described herein, the term "IC 50"IC" refers to the half-inhibitory concentration (or half-inhibitory rate). It is a very important data in the standard curve of indirect competitive ELISA. The standard curve is an S-shaped curve. In icELISA, the OD value of the control group without adding drugs is defined as B0, and the OD value of the experimental group with the addition of drugs is B. B / B0% is called the binding rate, and the concentration of the drug corresponding to 50% of the binding rate is called IC 50 . Generally, the smaller the value of IC 50 , the stronger the inhibitory effect of the drug.

[0062] As used herein, the term "tumor" includes all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.

[0063] As described herein, the term "cancer" includes diseases of skin tissue, organs, blood and blood vessels, such as, but not limited to, bladder cancer, bone cancer, blood cancer, brain cancer, breast cancer, cervical cancer, chest cancer, colon cancer, endometrial cancer, esophageal cancer, eye cancer, head cancer, kidney cancer, liver cancer, lymph node cancer, lung cancer, mouth cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, stomach cancer, testicular cancer, throat cancer, and uterine cancer. Specific cancers include, but are not limited to, advanced malignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastases, glioblastoma multiforme, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant glioma, pleomorphic xanthoastrocytoma, pleomorphic oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D colorectal cancer, unresectable colorectal cancer, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karyotypically acute myeloblasts leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse large B-cell lymphoma, low grade follicular lymphoma, malignant melanoma, malignant mesothelioma, malignant pleural mesothelioma syndrome, peritoneal cancer, papillary serous carcinoma, gynecological sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressiva, hormone refractory prostate cancer, high risk resected soft tissue sarcoma, unresectable hepatocellular carcinoma, Waldenstrom's macroglobulinemia, and indolent myeloma, inert myeloma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, urachal cancer, papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, and leiomyoma.

[0064] As described herein, expression of Ki-67 is closely related to breast cancer proliferation in the development of breast cancer, and expression of Ki-67 is a known prognostic and outcome indicator. Tumors can be classified according to Ki-67 index, and tumors with high Ki-67 index have a large number of proliferating cells, and thus can grow faster. Ki-67 can be detected by immunohistochemistry (IHC) method at present.

[0065] As described herein, Foxp3 (forkhead box P3) is a member of the forkhead transcription factor family. Expression of Foxp3 is associated with poor prognosis. Foxp3 has been widely recognized as a gene associated with breast cancer and prostate cancer in in vitro and in vivo studies.

[0066] As described herein, indoleamine 2,3-dioxygenase 1 (IDO-1) is a tryptophan catabolism enzyme, and IDO-1 is considered not only an immunomodulator during pregnancy, but also an immunomodulator in autoimmune diseases, chronic inflammation, and tumor immunity. In addition, IDO-1 has been considered a novel cancer immunotherapy target in recent years.

[0067] As described herein, Immunoglobulin kappa constant (IGKC) can now be used as a single and powerful immunomarker for predicting metastasis-free survival and chemotherapy response.

[0068] In at least one embodiment of the present disclosure, an effective amount of the duloxetine and the chemotherapeutic agent can be administered to an individual in need thereof.

[0069] In at least one embodiment of the present disclosure, the chemotherapeutic agent can be administered to the individual first, and then the duloxetine is administered.

[0070] In at least one embodiment of the present disclosure, the cancer can be at least one selected from the group consisting of breast cancer, non-small cell lung cancer, pancreatic cancer, liver cancer, and glioblastoma.

[0071] In at least one embodiment of the present disclosure, the breast cancer can be triple-negative breast cancer.

[0072] In at least one embodiment of the present disclosure, the chemotherapeutic agent can be at least one selected from the group consisting of an alkylating antineoplastic agent, an antimitotic agent, a DNA intercalating agent, a topoisomerase inhibitor, a DNA cleaving agent, an antimetabolites agent, and a tyrosine kinase inhibitor.

[0073] In at least one embodiment of the present disclosure, the chemotherapeutic drug can comprise an anti-mitotic agent, and the cancer is at least one selected from the group consisting of breast cancer, non-small cell lung cancer, liver cancer, and glioblastoma. In some embodiments, the anti-mitotic agent can be at least one selected from the group consisting of Docetaxel, Vinblastine, Vincristine, and Hupehenine. In at least one embodiment of the present disclosure, the chemotherapeutic drug can be Docetaxel, and the cancer is at least one selected from the group consisting of breast cancer, non-small cell lung cancer, liver cancer, and glioblastoma.

[0074] In at least one embodiment of the present disclosure, the chemotherapeutic drug can comprise an alkylating antineoplastic agent, and the cancer can be at least one selected from the group consisting of breast cancer, non-small cell lung cancer, pancreatic cancer, liver cancer, and glioblastoma. In some embodiments, the alkylating antineoplastic agent can be at least one selected from the group consisting of Cisplatin, Cyclophosphamide, Temozolomide, Nitrogen mustards, Chlormethine, Uramustine, Melphalan, Chlorambucil, Ifosfamide, Bendamustine, Nitrosoureas, Carmustine, Lomustine, Streptozocin, Alkyl sulfonates, Busulfan, Platinum, Carboplatin, Dicycloplatin, Eptaplatin, Lobaplatin, Miriplatin, Nedaplatin, Oxaliplatin, Picoplatin, Satraplatin, Triplatin tetranitrate, Triazenes, Dacarbazine, Mitozolomide, Procarbazine, and Altretamine. In some embodiments, the alkylating antineoplastic agent can be Cisplatin, and the cancer can be at least one selected from the group consisting of breast cancer, pancreatic cancer, and liver cancer. In some embodiments, the chemotherapeutic drug can be Cyclophosphamide, and the cancer can be breast cancer and / or glioblastoma. In some embodiments, the chemotherapeutic drug can be Temozolomide, and the cancer can be breast cancer and / or non-small cell lung cancer.

[0075] In at least one embodiment of the present disclosure, the chemotherapeutic drug can comprise an anti-metabolite agent, and the cancer can be at least one selected from the group consisting of breast cancer, non-small cell lung cancer, liver cancer, and glioblastoma. In some embodiments, the anti-metabolite agent is at least one selected from the group consisting of 5-Fluorouracil, Cytarabine, 6-Mercaptopurine, and Methotrexate. In some embodiments, the anti-metabolite agent can be 5-Fluorouracil, and the cancer can be at least one selected from the group consisting of breast cancer, non-small cell lung cancer, liver cancer, and glioblastoma.

[0076] In at least one embodiment of the present disclosure, the chemotherapeutic drug can comprise a DNA intercalator or a DNA cleaving agent, and the cancer can be at least one selected from the group consisting of breast cancer, non-small cell lung cancer, pancreatic cancer, and liver cancer. In some embodiments, the DNA intercalator can be at least one selected from the group consisting of Doxorubicin, Actinomycin D, and Daunorubicin, and the DNA cleaving agent can be at least one selected from the group consisting of Doxorubicin, Bleomycin, and Daunorubicin. In some embodiments, the DNA intercalator or the DNA cleaving agent can be Doxorubicin, and the cancer can be at least one selected from the group consisting of breast cancer, non-small cell lung cancer, pancreatic cancer, and liver cancer.

[0077] In at least one embodiment of the present disclosure, the chemotherapeutic drug can comprise a tyrosine kinase inhibitor, and the cancer can be at least one selected from the group consisting of breast cancer, non-small cell lung cancer, pancreatic cancer, liver cancer, and glioblastoma. In some embodiments, the tyrosine kinase inhibitor can be at least one selected from the group consisting of Osimertinib, Sorafenib, Imatinib, Sunitinib, Erlotinib, Gefitinib, Dasatinib, and Lapatinib. In some embodiments, the tyrosine kinase inhibitor can be Osimertinib, and the cancer can be at least one selected from the group consisting of breast cancer, non-small cell lung cancer, pancreatic cancer, and glioblastoma. In some embodiments, the tyrosine kinase inhibitor can be Sorafenib, and the cancer can be non-small cell lung cancer and / or liver cancer.

[0078] In at least one embodiment of the present disclosure, the chemotherapeutic drug can include a topoisomerase inhibitor, but does not include etoposide. In some embodiments, the topoisomerase inhibitor can be at least one selected from the group consisting of camptothecin, topotecan, irinotecan, and podophyllotoxin. In at least one embodiment of the present disclosure, the topoisomerase inhibitor includes a type 1 topoisomerase inhibitor, but does not include a type 2 topoisomerase inhibitor. In some embodiments, the topoisomerase inhibitor does not include etoposide.

[0079] In at least one embodiment of the present disclosure, the pharmaceutical composition can include a pharmaceutically acceptable carrier or excipient.

[0080] In at least one embodiment of the present disclosure, the pharmaceutical composition can be formulated into a dosage form selected from the group consisting of a tablet, a capsule, an injection, a lozenge, a powder, a granule, and any combination thereof.

[0081] In at least one embodiment of the present disclosure, the chemotherapeutic drug can be at least one selected from the group consisting of docetaxel, cisplatin, cyclophosphamide, 5-fluorouracil, doxorubicin, temozolomide, osimertinib, sorafenib, and any combination thereof.

[0082] In at least one embodiment of the present disclosure, the pharmaceutical composition of the present disclosure can reduce Ki-67.

[0083] In at least one embodiment of the present disclosure, the pharmaceutical composition of the present disclosure can reduce a tumor by at least 40% (for example, but not limited to, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%).

[0084] In at least one embodiment of the present disclosure, the pharmaceutical composition of the present disclosure shows that 1) doxepin combined with polyeneposide produces better efficacy on triple negative breast cancer, non-small cell lung cancer, liver cancer and glioblastoma than polyeneposide alone; 2) doxepin combined with cisplatin produces better efficacy on triple negative breast cancer, pancreatic cancer and liver cancer than cisplatin alone; 3) doxepin combined with cyclophosphamide produces better efficacy on triple negative breast cancer and glioblastoma than cyclophosphamide alone; 4) doxepin combined with 5-fluorouracil produces better efficacy on triple negative breast cancer, non-small cell lung cancer, liver cancer and glioblastoma than 5-fluorouracil alone; 5) doxepin combined with doxorubicin produces better efficacy on triple negative breast cancer, non-small cell lung cancer, pancreatic cancer and liver cancer than doxorubicin alone; 6) doxepin combined with temozolomide produces better efficacy on triple negative breast cancer and non-small cell lung cancer than temozolomide alone; 7) doxepin combined with osimertinib produces better efficacy on triple negative breast cancer, non-small cell lung cancer, pancreatic cancer and glioblastoma than osimertinib alone; 8) doxepin combined with sorafenib produces better efficacy on non-small cell lung cancer and liver cancer than sorafenib alone; and 9) doxepin combined with etoposide does not produce better efficacy on triple negative breast cancer, non-small cell lung cancer, pancreatic cancer, liver cancer and glioblastoma than etoposide alone.

[0085] In at least one embodiment of the present disclosure, the results show that doxepin + NACT combination can effectively improve tumor shrinkage, increase the number of complete response individuals, and reduce Ki-67. In some embodiments of the present disclosure, the relative tumor reduction of the doxepin + NACT group is 22.65%, the tumor shrinkage rate of the doxepin + NACT group is higher than that of the NACT group, the tumor shrinkage ratio of the doxepin + NACT group is higher than that of the NACT group, the proportion of CR individuals in the doxepin + NACT group (42.9%) is higher than that of the NACT group (0%), individuals with less Foxp3 concentration before treatment (Foxp3-V1) are more likely to achieve better tumor shrinkage, individuals with less IDO-1 concentration before treatment (IDO-1-V1) are more likely to achieve better tumor shrinkage, and individuals with less IGKC concentration after treatment (IGKC-V18) are more likely to achieve better tumor shrinkage.

[0086] EMBODIMENT

[0087] Exemplary embodiments of the present disclosure are further described in the following embodiments, which should not be construed as limiting the scope of the present disclosure.

[0088] In the present disclosure, the drug concentrations of the embodiments are listed in Table 1, and the cancer cell model information is listed in Table 2.

[0089] Table 1. Example drug concentrations in the present disclosure

[0090] Table 2. Cancer cell models in the present disclosure

[0091] Example 1. Establishment of cell lines and cancer cell survival analysis method

[0092] Please refer to Table 2. The cell lines of different cancer types were subcultured, and after calculating the cell number, 1x10 4Cell number, 24 hours later, drug was added (as shown in Table 1), 72 hours later, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) was added, 90 minutes later, 570 nm was detected. Data was calculated as cell inhibition rate (as 100% - cell survival rate). If the G5 value is higher than the G1 value, or the G4 value is higher than the G2 value, the combination result is better than the use of chemotherapy drugs alone. The results are shown in Figures 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 and 31, and refer to Tables 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13 below, and the results of Example 1 are shown in Table 13. The results show that: 1) compared with the use of docetaxel alone, docetaxel combined with duloxetine has better efficacy on triple-negative breast cancer, non-small cell lung cancer, liver cancer and glioblastoma; 2) compared with the use of cisplatin alone, cisplatin combined with duloxetine has better efficacy on triple-negative breast cancer, pancreatic cancer and liver cancer; 3) compared with the use of cyclophosphamide alone, cyclophosphamide combined with duloxetine has better efficacy on triple-negative breast cancer and glioblastoma; 4) compared with the use of 5-fluorouracil alone, 5-fluorouracil combined with duloxetine has better efficacy on triple-negative breast cancer, non-small cell lung cancer, liver cancer and glioblastoma; 5) compared with the use of doxorubicin alone, doxorubicin combined with duloxetine has better efficacy on triple-negative breast cancer, non-small cell lung cancer, pancreatic cancer and liver cancer; 6) compared with the use of temozolomide alone, temozolomide combined with duloxetine has better efficacy on triple-negative breast cancer and non-small cell lung cancer; 7) compared with the use of osimertinib alone, osimertinib combined with duloxetine has better efficacy on triple-negative breast cancer, non-small cell lung cancer, pancreatic cancer and glioblastoma; and 8) compared with the use of sorafenib alone, sorafenib combined with duloxetine has better efficacy on non-small cell lung cancer and liver cancer; and 9) compared with the use of etoposide alone, etoposide combined with duloxetine does not have better efficacy on the treatment of triple-negative breast cancer, non-small cell lung cancer, pancreatic cancer, liver cancer and glioblastoma.

[0093] Table 3 Results of docetaxel and duloxetine combination in the present disclosure

[0094] Y: better than the use of chemotherapy drugs alone

[0095] N: no better than the use of chemotherapy drugs alone

[0096] Table 4 Results of cisplatin and duloxetine combination in the present disclosure

[0097] Y: better than the chemotherapeutic agent alone

[0098] N: not better than the chemotherapeutic agent alone

[0099] Table 5 Results of cyclophosphamide (IC50) and duloxetine combination in the present disclosure

[0100] Y: better than the chemotherapeutic agent alone

[0101] N: not better than the chemotherapeutic agent alone

[0102] Table 6 Results of 5-fluorouracil (1 / 2 IC50) and duloxetine combination in the present disclosure

[0103] Y: better than the chemotherapeutic agent alone

[0104] N: not better than the chemotherapeutic agent alone

[0105] Table 7 Results of doxorubicin and duloxetine combination in the present disclosure

[0106] Y: better than the chemotherapeutic agent alone

[0107] N: not better than the chemotherapeutic agent alone

[0108] Table 8 Results of temozolomide and duloxetine combination in the present disclosure

[0109] Y: better than the chemotherapeutic agent alone

[0110] N: not better than the chemotherapeutic agent alone

[0111] Table 9 Results of osimertinib (IC50) and duloxetine combination in the present disclosure 50

[0112] Y: better than the chemotherapeutic agent alone

[0113] N: not better than the chemotherapeutic agent alone

[0114] Table 10 Results of osimertinib (1 / 2 IC50) and duloxetine combination in the present disclosure 50

[0115] Y: better than the chemotherapeutic agent alone

[0116] N: not better than the chemotherapeutic agent alone

[0117] ​​Table 11 Results of sorafenib (1 / 2 IC 50 ) and duloxetine combination in the present disclosure

[0118] Y: better than the chemotherapeutic agent alone

[0119] N: not better than the chemotherapeutic agent alone

[0120] Table 12 Results of etoposide and duloxetine combination in the present disclosure

[0121] Table 13 Summary table of cancer cell survival analysis in the present disclosure

[0122] Y: better than the chemotherapeutic agent alone

[0123] Example 2 Clinical trial

[0124] Inclusion criteria: female with newly diagnosed stage II triple negative breast cancer with tumor > 2 cm and age > 20 years old without mastectomy or systemic chemotherapy. NACT: neoadjuvant chemotherapy with 4 cycles of docetaxel followed by 4 cycles of cyclophosphamide and doxorubicin, and finally surgical resection of the lesion. Duloxetine + NACT: duloxetine was administered one week before the chemotherapy after clinical inclusion, and the drug was adjusted two weeks after the end of the chemotherapy, and finally surgical resection of the lesion

[0125] Method for detecting Foxp3 expression and IDO-1 expression

[0126] The pretreatment process is described as follows. First, collect 4 tubes of whole blood samples with EDTA-containing anticoagulant purple head tube, and perform pretreatment at room temperature on the same day. Centrifuge (340g, 5min) two tubes of whole blood of the subject, remove the supernatant (plasma), and place it in a 2mL microcentrifuge tube. Label the sample number, take a photo, detect whether there is hemolysis, and store it in a -80°C refrigerator. After the 4 tubes of samples of the same subject are collected, perform ELISA test. The third tube of whole blood is not centrifuged and is stored at 4°C for standby. The fourth tube is pretreated before flow cytometry experiment. Take 1X RBC (red blood cell) lysis buffer, dilute it 10 times with deionized and distilled water (dd water). Mix the whole blood gently and uniformly, take 500μl, and add 9.5mL 1X RBC lysis buffer. Mix thoroughly, avoid light, and react for 15min. After the reaction is completed, centrifuge (340g, 5min) to remove the supernatant. Add 200μl of staining buffer to disperse the cells on the tube wall, and transfer them to a 1.75mL microcentrifuge tube. Centrifuge (340g, 5min) to remove the supernatant. Add 0.5mL of fixing buffer and react in the dark for 20min. After fixing is completed, centrifuge (340g, 5min) to remove the supernatant. Add 0.5mL of staining buffer and store it at 4°C for preservation. The antibodies used in the present disclosure are listed in Table 14. The chemicals used in the present disclosure are listed in Table 15.

[0127] Staining and machine

[0128] Centrifuge (340g, 5min) the pretreated sample to remove the supernatant, add 300μl of staining buffer to resuspend it again, mix it uniformly, and then divide it equally into three tubes, each with a volume of 100μl.

[0129] Use the second tube (permeabilization) to perform Foxp3 staining. Centrifuge (340g, 5min) 100μl of the sample to remove the supernatant. Add 200μl of intracellular staining permeabilization buffer, mix thoroughly to permeabilize, stand for 10min, centrifuge (340g, 5min) to remove the supernatant. After resuspending with 100μl of staining buffer, take the corresponding staining volume of antibody Foxp3, mix it uniformly, and react in the dark for 20min. Add 400μl of staining buffer to make the volume 500μl when put on the machine. Analyze it by flow cytometry (Novocyte 3000, Agilent), and select 10000 white blood cells for analysis.

[0130] For IDO-1 staining, 100 μl of sample was centrifuged (340 g, 5 min), and the supernatant was removed. 200 μl of intracellular staining permeabilization buffer was added, and the sample was mixed well and permeabilized, and then allowed to stand for 10 min. After centrifugation (340 g, 5 min), the supernatant was removed. After resuspension with 100 μl of staining buffer, the corresponding staining volume of antibody IDO-1 was added, and the sample was mixed well and allowed to stand in the dark for 20 min. 400 μl of staining buffer was added, and the sample was analyzed by flow cytometry (Novocyte 3000, Agilent). 10,000 white blood cells were selected for analysis.

[0131] Table 14 Antibodies used in the present disclosure

[0132] Table 15 Chemicals used in the present disclosure

[0133] Detection method of IGKC expression

[0134] The method is described in detail as follows. Four tubes of whole blood samples were collected in EDTA-containing anticoagulant purple head tubes, and the pretreatment was performed at room temperature on the same day. Two tubes of whole blood of the patient were centrifuged (340 g, 5 min), and the plasma was removed and placed in a 2 mL microcentrifuge tube. The sample number was labeled, and a photograph was taken to check for hemolysis. The target content was analyzed by an ELISA kit, and the absorbance value at 450 nm was detected by a spectrophotometer (M200 PRO, TECAN). The experiment was completed in a 96-well plate, and the standard and sample were arranged in duplicate in the plate. According to the known concentration of the standard after dilution, a function equation (calculated by software, usually approximated to a binary first-order equation graph) can be obtained with the corresponding absorbance value. The OD value of the sample was brought into the equation, and the concentration value of the sample was obtained.

[0135] Exclusion criteria, the following personnel are not suitable for participating in the examples of the present disclosure:

[0136] History of chemotherapy for any malignant tumor; history of radiotherapy for breast cancer; second primary malignant tumor that was not relieved five years ago, but non-melanoma skin cancer or cervical carcinoma in situ was excluded; poor general condition (not suitable for receiving dose-intensive, dose-intensified anthracycline (taxane) targeted drug combination chemotherapy); history of suicide or self-injury within the past five years.

[0137] The following medications are not suitable for participation in the disclosed embodiments: Monoamine oxidase inhibitors (MAO-I) within 14 days prior to enrollment. Concomitant use of phenothiazines (including thioridazine), propafenone, flecainide, triptans, MAO-I, selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), or tricyclic antidepressants.

[0138] Individuals with the following cardiovascular diseases or individuals with autoimmune diseases or using immunosuppressive agents (except steroids) are not suitable for participation in the disclosed embodiments: symptomatic congestive heart failure, myocardial infarction, severe or unstable angina pectoris (within 6 months prior to the screening day), high risk of arrhythmia, uncontrolled hypertension.

[0139] The following individuals are not suitable for participation in the disclosed embodiments: patients with the following diseases: liver insufficiency, chronic liver disease, severe renal disease; symptomatic chronic lung disease, symptomatic restrictive lung disease, interstitial pneumonitis or other abnormalities of lung function that can affect the safety of the patient. Uncontrolled angle-closure glaucoma or clinically significant coagulopathy; patients with uncontrolled bacterial or viral infections or active or recent (within 6 months) fungal infection at the time of enrollment; active central nervous system disease at the time of enrollment; currently having a primary psychiatric disorder (schizophrenia, psychosis) or a history of suicidal ideation, bipolar disorder or seizure disorder.

[0140] Serologically positive for HIV infection or HIV positive, HBV or HCV acute phase; patients known to be hypersensitive to any of the study treatment drugs, including the excipients of the study drug. History of alcohol abuse in the past year, i.e. more than 14 standard drinks per week for men and more than 7 standard drinks per week for women (one standard drink is defined as 360 ml of beer, 150 ml of wine or 45 ml of 40% distilled spirits, such as rum, whiskey, brandy, etc.).

[0141] Patients who cannot use effective contraception from screening until 6 months after the end of the study and after withdrawal from the study. Pregnant or lactating women, or women planning to become pregnant or to breastfeed. Any condition that, in the investigator's opinion, would affect the assessment of study treatment, patient safety, or interpretation of study results.

[0142] Unless otherwise approved by the principal investigator, individuals who have participated in another clinical trial and received investigational products within 28 days prior to enrollment in the current example, or who have received pre-study cellular therapy / transplantation, are not eligible to participate in the disclosed examples.

[0143] Referring to FIG. 32, the relative tumor reduction in the duloxetine + NACT group was 22.65%. Referring to FIG. 33, the tumor shrinkage rate in the duloxetine + NACT group was higher than that in the NACT group. Referring to FIG. 34, the tumor shrinkage waterfall plot shows that the tumor shrinkage ratio in the duloxetine + NACT group was higher than that in the NACT group. Referring to FIGS. 35 and 36, the results show that the proportion of individuals with CR (42.9%) in the duloxetine + NACT group was higher than that in the NACT group (0%). Referring to FIG. 37, the results show that the Foxp3 expression in peripheral blood mononuclear cells before treatment (upper panel) in the duloxetine + NACT group had a trend of negative correlation with the tumor shrinkage rate (R2=0.728, P=0.031, lower panel), indicating that individuals with a lower Foxp3 concentration before treatment (Foxp3-V1) were more likely to achieve better tumor shrinkage. Referring to FIG. 38, the IDO-1 expression in peripheral blood mononuclear cells before treatment (upper panel) in the duloxetine + NACT group had a trend of negative correlation with the tumor shrinkage rate (R2=0.579, P=0.079, lower panel), indicating that individuals with a lower IDO-1 concentration before treatment (IDO-1-V1) were more likely to achieve better tumor shrinkage. Referring to FIG. 39, the higher IGKC expression in peripheral blood mononuclear cells after treatment (upper panel) in the duloxetine + NACT group had a trend of negative correlation with the tumor shrinkage rate, indicating that individuals with a lower IGKC concentration after treatment (IGKC-V18) were more likely to achieve better tumor shrinkage (R2=0.796, P=0.017, lower panel).

[0144] As shown in Table 15 below, in the disclosed examples, the baseline data of the individuals in the NACT group (N=6) and the duloxetine + NACT group (N=7) before treatment were similar.

[0145] Table 16 Baseline data of the NACT group (N=6) and the duloxetine + NACT group (N=7) before treatment

[0146] ECOG: Eastern Cooperative Oncology Group. TNM IIa: T0-2; N0-1; M0; TNM IIb: T 2-3; N 0-1; M0; TNM IIIc: any of T, N3, and M0. SD: standard deviation

[0147] As shown in Table 17 below, in the present embodiment, the medication compliance of the duloxetine + NACT group is about 80 to 90%.

[0148] Table 17 Medication compliance of individuals in duloxetine + NACT group (N = 7)

[0149] SD: standard deviation

[0150] As shown in Table 18 below, in the present embodiment, after treatment, the tumor size, blood pressure, and Ki-67 (%) of the duloxetine + NACT group are significantly reduced. According to Table 19 below, the average tumor shrinkage rate of the duloxetine + NACT group is higher than that of the NACT group.

[0151] Table 18 Changes in body weight, blood pressure, and tumor size after treatment in NACT group and duloxetine + NACT group

[0152] *Since there is a lack of ki-67 data of one individual in the NACT group, statistical analysis is only performed for five individuals.

[0153] Table 19 Average tumor shrinkage rate in NACT group and duloxetine + NACT group

[0154] NACT: neoadjuvant chemotherapy

[0155] Referring to FIG. 35 and Table 20, it can be seen that the NACT group is only partially responsive. In the duloxetine + NACT group, three individuals are completely responsive, and four individuals are partially responsive. It can be seen that the duloxetine + NACT group has a better effect than the NACT group.

[0156] Table 20 Objective response rate and disease control rate

[0157] This table only includes individuals who had assessable RECIST response. CR: complete response; PR: partial response; SD: stable disease. PD: progressive disease. NACT: neoadjuvant chemotherapy. ORR data from computed tomography (CT) imaging results.

[0158] Referring to Tables 21, 22 and 23, the hematological reports, biochemical reports and urine analysis of the duloxetine + NACT group showed that the duloxetine + NACT intervention had no adverse effects on the individuals.

[0159] Table 21 Hematological reports of the duloxetine + NACT group

[0160] RBC: red blood cell. WBC: white blood cell. DC: differential count. Neu: neutrophil. Eos: eosinophil. Baso: basophil. Mono: monocyte. RDW: red cell distribution width. MCV: mean corpuscular volume. MCHC: mean corpuscular hemoglobin concentration. ANC: absolute neutrophil count. SD: standard deviation.

[0161] Table 22 Biochemical reports of the duloxetine + NACT group

[0162] BUN: blood urea nitrogen. TG: triglyceride. SD: standard deviation.

[0163] Table 23 Urine analysis of the duloxetine + NACT group

[0164] SD: standard deviation.

[0165] The results of this example show that the duloxetine + NACT combination can effectively increase the tumor shrinkage rate, increase the number of complete response individuals, and reduce Ki-67.

[0166] Those of ordinary skill in the art will readily observe that without departing from the teachings of the present application that various modifications, and changes can be made thereto. It is therefore intended that the above disclosed teachings be interpreted as only limiting examples of the present application and be limited only by the scope of the appended claims.

Claims

1. Use of duloxetine and a chemotherapeutic agent for the manufacture of a pharmaceutical composition for treating or preventing cancer.

2. The use of claim 1, comprising administering to a subject in need thereof an effective amount of the duloxetine and the chemotherapeutic agent.

3. The use of claim 2, wherein, The chemotherapeutic agent is administered to the subject prior to the duloxetine.

4. The use of claim 1, wherein, The cancer is at least one selected from the group consisting of breast cancer, non-small cell lung cancer, pancreatic cancer, liver cancer, and glioblastoma.

5. The use of claim 4, wherein, The breast cancer is triple-negative breast cancer.

6. The use of claim 1, wherein, The chemotherapeutic agent is at least one selected from the group consisting of an alkylating antineoplastic agent, an antimitotic agent, a DNA intercalator, a topoisomerase inhibitor, a DNA cleaving agent, an antimetabolite, and a tyrosine kinase inhibitor.

7. The use of claim 6, wherein, The chemotherapeutic agent comprises an antimitotic agent, and the cancer is at least one selected from the group consisting of breast cancer, non-small cell lung cancer, liver cancer, and glioblastoma.

8. The use of claim 7, wherein, The antimitotic agent is at least one selected from the group consisting of docetaxel, vinblastine, vincristine, and hainwoodine.

9. The use of claim 6, wherein, The chemotherapeutic agent comprises an alkylating antineoplastic agent, and the cancer is at least one selected from the group consisting of breast cancer, non-small cell lung cancer, pancreatic cancer, liver cancer, and glioblastoma.

10. The use of claim 9, wherein, The alkylating antineoplastic agent is at least one selected from the group consisting of cisplatin, cyclophosphamide, temozolomide, mechlorethamine, mechlorethamine, uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, nitrosoureas, carmustine, cyclophosphamide, streptozotocin, alkyl sulfonate, busulfan, platinum, carboplatin, dicycloplatin, iproplatin, lobaplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin, triplatin, triazenes, dacarbazine, mitozolomide, procarbazine, and hexamethylmelamine.

11. The use of claim 6, wherein, The chemotherapeutic agent comprises an antimetabolite, and the cancer is at least one selected from the group consisting of breast cancer, non-small cell lung cancer, liver cancer, and glioblastoma.

12. The use of claim 11, wherein, The antimetabolite is at least one selected from the group consisting of 5-fluorouracil, cytarabine, 6-mercaptopurine, and methotrexate.

13. The use of claim 6, wherein, The chemotherapeutic agent comprises a DNA intercalator or a DNA cleaving agent, and the cancer is at least one selected from the group consisting of breast cancer, non-small cell lung cancer, pancreatic cancer, and liver cancer.

14. The use of claim 13, wherein, The DNA intercalator is at least one selected from the group consisting of doxorubicin, dactinomycin, and daunorubicin, and the DNA cleaving agent is at least one selected from the group consisting of doxorubicin, bleomycin, and daunorubicin.

15. The use of claim 6, wherein, The chemotherapeutic agent comprises a tyrosine kinase inhibitor, and the cancer is at least one selected from the group consisting of breast cancer, non-small cell lung cancer, pancreatic cancer, liver cancer, and glioblastoma.

16. The use of claim 15, wherein, The tyrosine kinase inhibitor is at least one selected from the group consisting of osimertinib, sorafenib, imatinib, sunitinib, erlotinib, gefitinib, dasatinib, and lapatinib.

17. The use of claim 6, wherein, The chemotherapeutic agent comprises a topoisomerase inhibitor, but does not comprise etoposide.

18. The use of claim 17, wherein, The topoisomerase inhibitor is at least one selected from the group consisting of camptothecin, topotecan, irinotecan, and podophyllotoxin.

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