CN-121971474-A - Application of SLC30A9 inhibitor in preparation of antitumor drugs

Abstract

The invention relates to application of an SLC30A9 inhibitor in preparation of anti-tumor drugs, and belongs to the technical field of biological medicines. The invention provides application of an SLC30A9 inhibitor in preparing an anti-tumor medicament. SLC30A9 expression down-regulates and activates cGAS-STING-NF- κB pathway, thereby promoting osteosarcoma cell apoptosis, enhancing MTX killing of osteosarcoma cell, and restoring sensitivity of osteosarcoma cell to MTX chemotherapy. Through the combined application of SLC30A9 knockdown, cGAS-STING-NF- κB channel agonist and MTX chemotherapy, the killing of MTX to osteosarcoma cells can be obviously enhanced, the proliferation of tumor cells can be inhibited and the treatment effect can be improved. The core effect of SLC30A9 in the chemotherapy drug resistance mechanism of osteosarcoma is clarified, and theoretical basis and technical support are provided for the follow-up development of targeted drugs aiming at the cGAS-STING-NF- κB pathway.

Inventors

• MA MENGJUN
• LI HONGYU
• YANG BIAO
• ZHUANG JIAHAO
• SONG YIHUI
• Mi Rujia
• YANG WEN
• LU YIXUAN
• LIU YINLIANG

Assignees

• 中山大学附属第八医院（深圳福田）

Dates

Publication Date

20260505

Application Date

20260206

Claims (10)

1. The application of SLC30A9 inhibitor in preparing antitumor medicine.
2. 2. The use of claim 1, wherein the medicament is a medicament that reduces resistance to methotrexate.
3. 3. The use of claim 1, wherein the tumor comprises osteosarcoma.
4. 4. The use of claim 1, wherein the SLC30A9 inhibitor comprises shRNA.
5. 5. The use according to claim 4, wherein the shRNA has a nucleotide sequence as set forth in SEQ ID No. 1 or 2.
6. 6. An antitumor agent comprising an SLC30A9 inhibitor.
7. 7. The medicament of claim 6, wherein the SLC30A9 inhibitor comprises shRNA.
8. 8. The medicament of claim 7, wherein the shRNA has a nucleotide sequence shown in SEQ ID No. 1 or 2.
9. 9. The medicament of claim 6, further comprising methotrexate and/or an interferon gene stimulatory protein agonist.
10. 10. The medicament of claim 9, wherein the interferon gene stimulatory protein agonist comprises STING-agonist3.

Description

Application of SLC30A9 inhibitor in preparation of antitumor drugs Technical Field The invention relates to the technical field of biological medicines, in particular to application of an SLC30A9 inhibitor in preparation of antitumor drugs. Background Osteosarcoma (Osteosarcoma, OS) is one of the most common primary malignant bone tumors, most of which occur in children and young adults between 10 and 30 years of age. The combined treatment of surgical excision and systemic chemotherapy significantly improves the survival rate of patients with non-metastatic osteosarcoma, with a survival rate of about 70%. Common chemotherapeutic drugs for osteosarcoma in clinic include Methotrexate (MTX), cisplatin (CISPLATIN), cyclophosphamide (Cyclophosphamide), doxorubicin (doxorubicin), and the like. Wherein MTX is widely applied to the first-line treatment scheme of osteosarcoma chemotherapy, thereby greatly improving the survival rate of osteosarcoma patients. However, drug resistance is gradually developed during MTX chemotherapy, which leads to further progression of osteosarcoma, and this problem seriously affects the prognosis of patients. The current mechanistic studies on MTX chemotherapy resistance remain lacking in systemicity and sufficient depth, which severely restricts the development of effective targeted therapeutic strategies clinically. Disclosure of Invention The invention aims to overcome the defects of the prior art and provide the application of the SLC30A9 inhibitor in preparing antitumor drugs. In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: In a first aspect, the invention provides the use of an SLC30A9 inhibitor in the manufacture of an anti-neoplastic medicament. The invention discovers that the expression of SLC30A9 is down-regulated to inhibit the drug resistance of osteosarcoma to methotrexate and reveals the key effect of the SLC30A9 in activating the cGAS-STING-NF- κB channel, and proposes to solve the drug resistance problem of osteosarcoma MTX based on the key effect. Further, the drug is a drug that reduces resistance to methotrexate. As a preferred embodiment of the present invention, the tumor comprises osteosarcoma. Further, the SLC30A9 inhibitor comprises shRNA. As a preferred embodiment of the invention, the nucleotide sequence of the shRNA is shown as SEQ ID NO. 1 or 2. In a second aspect, the invention provides an anti-neoplastic agent characterized in that the agent comprises an SLC30A9 inhibitor. Further, the SLC30A9 inhibitor comprises shRNA. As a preferred embodiment of the invention, the nucleotide sequence of the shRNA is shown as SEQ ID NO. 1 or 2. Further, the medicament also contains methotrexate and/or an interferon gene stimulatory protein agonist. As a preferred embodiment of the present invention, the interferon gene stimulatory protein agonists include STING-agonist3. Compared with the prior art, the invention has the beneficial effects that: (1) The targeted regulation of SLC30A9 is that SLC30A9 expression down regulates and activates cGAS-STING-NF- κB channel, thereby promoting osteosarcoma cell apoptosis, enhancing MTX killing on osteosarcoma cell, restoring sensitivity of osteosarcoma cell to MTX chemotherapy, effectively blocking drug resistance development from molecular level, the accurate treatment mode avoids extensive damage to normal cell by traditional treatment, and obviously improves safety and effectiveness of treatment. (2) The combined treatment strategy is that through combined application of SLC30A9 knockdown, cGAS-STING-NF- κB channel agonist and MTX chemotherapy, the killing of MTX to osteosarcoma cells can be obviously enhanced, the proliferation of tumor cells can be inhibited and the treatment effect can be improved, compared with a single chemotherapy method, the proliferation of tumor cells can be inhibited to a greater extent, the treatment effect can be improved, and a new solution is provided for improving the chemotherapy sensitivity and the treatment effect of osteosarcoma patients. (3) The invention confirms the core role of SLC30A9 in the chemotherapy drug resistance mechanism of osteosarcoma, further reveals the downstream molecular regulation network, provides theoretical basis and technical support for the follow-up development of targeted drugs aiming at the cGAS-STING-NF- κB pathway, and provides theoretical basis and potential targets for the clinical development of novel therapeutic drugs aiming at interferon gene stimulating protein (STING) agonists. Drawings FIG. 1 is a graph demonstrating the efficiency of the SLC30A9 knockdown by osteosarcoma cells. Wherein A is qPCR to detect the SLC30A9 knockdown efficiency of osteosarcoma cells (U2 OS), and B is Westernblot to detect the SLC30A9 knockdown efficiency of osteosarcoma cells (U2 OS). FIG. 2 is a Westernblot analysis result of activation of the cGAS-STING-NF- κB pathway by SLC30A 9. FIG. 3 is a flow cytometry plot of apop