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Application of drug combination of ENPP1 inhibitor and anticancer drug to preparation of antitumor drug

A technology of anti-tumor drugs and anti-cancer drugs, which is applied in the field of medicine, can solve the problems of ENPP1 tumor metabolism regulating tumor drug resistance, etc., and achieve high-efficiency clinical application prospects, delay drug resistance, and inhibit growth.

Active Publication Date: 2020-11-24
SHANGHAI JIAOTONG UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

ENPP1 is highly expressed in bone tissue and cartilage, and its product pyrophosphate (PPi) is mainly involved in the formation of hydroxyapatite, the inorganic component with the highest content in human bone tissue. Therefore, current international research focuses on the regulation of pyrophosphate levels by ENPP1 to promote bone mineralization. calcification and soft tissue calcification, etc., but there is no role of ENPP1 in the regulation of tumor metabolism and the generation of tumor drug resistance

Method used

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  • Application of drug combination of ENPP1 inhibitor and anticancer drug to preparation of antitumor drug
  • Application of drug combination of ENPP1 inhibitor and anticancer drug to preparation of antitumor drug
  • Application of drug combination of ENPP1 inhibitor and anticancer drug to preparation of antitumor drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1. The effect of siENPP1 on inhibiting lung cancer cells, especially significantly inhibiting the migration of drug-resistant lung cancer cells was explored by transwell experiments, and the specific steps are as follows:

[0024] (1) After resuscitation, lung cancer and its lung cancer drug-resistant cells that were stably grown in the 2-4 generations were taken, digested with 0.25% trypsin, and inoculated into a 6-well plate with a complete medium to make a single-cell suspension. At 37°C, 5% CO 2 Incubate in a constant temperature cell incubator to allow it to grow and adhere to the wall.

[0025] (2) Lung cancer and its drug-resistant cells were divided into mock group and siENPP1 group, and siNC and siENPP1 were added to corresponding cells after being entrapped in liposomes. Put the culture plate into the incubator and incubate for 24-48h, digest with 0.25% trypsin, make a single cell suspension with serum-free basal medium, adjust the cell density to 5×1...

Embodiment 2

[0037] Example 2. siENPP1 and ENPP1 inhibitor SYL-001 inhibit lung cancer cells, especially significantly inhibit the proliferation of drug-resistant cells

[0038] Specific steps are as follows:

[0039] (1) Take lung cancer and drug-resistant cells that grow stably for 2 to 4 passages after resuscitation, make a single cell suspension and inoculate them in a 96-well plate with a cell density of 3000 cells / well, and place at 37°C, 5% CO2 incubator to allow it to grow adherently.

[0040] (2) siENPP1: The cell confluence was observed under a microscope to reach about 40-60%, and the lung cancer and its drug-resistant cells were divided into mock group and siENPP1 group. siNC and siENPP1 were added to the corresponding cells after being entrapped in liposomes, and the culture plate was put into the Incucyte live cell detector for real-time monitoring for 72 hours.

[0041](3) SYL-001: Lung cancer and its drug-resistant cells were divided into DMSO group and SYL-001 group. The...

Embodiment 3

[0043] Example 3. The combination of siENPP1 and ENPP1 inhibitor SYL-001 with the cancer chemotherapy drug cisplatin exerts a synergistic anticancer effect

[0044] Specific steps are as follows:

[0045] (1) Take lung cancer, breast cancer, cervical cancer, and colorectal cancer cells that have grown stably for 2 to 4 passages after resuscitation, and make single-cell suspensions and inoculate them in 96-well plates at a cell density of 3000 cells / well. 37°C, 5% CO2 incubator to make it grow and adhere to the wall.

[0046] (2) Observe under the microscope that the cell confluence reaches about 40-60%, and set the tumor cells as DMSO group, chemotherapy drug group cisplatin, siENPP1 group, SYL-001 group, chemotherapy drug group+siENPP group and chemotherapy drug group +SYL-001 group. Drugs or siRNA were added to the corresponding cells, and the culture plate was put into the Incucyte Live Cell Detector for real-time monitoring for 72 hours.

[0047] (3) After 72 hours of d...

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Abstract

The invention provides application of a drug combination of an ENPP1 inhibitor and anticancer drug to preparation of antitumor drug. The ENPP1 inhibitor comprises SYL-001 or carrier-delivered siENPP1,shENPP1 and CRISPR-Cas9 preparations; and the anticancer drug comprises cis-platinum, tarceva, gefitinib or osimertinib. According to the invention, the results that the ENPP1 inhibitor and chemotherapeutic drug of cis-platinum and lung cancer targeted drug (tarceva, gefitinib and osimertinib) cooperate to achieve the antitumor effects; the occurrence of phenomena of drug resistance and recurrence are obviously inhibited and delayed; and the cancer includes colorectal cancer, cervical cancer and lung cancer. More importantly, the ENPP1 inhibitor particularly and significantly inhibits drug-resistant recurrent lung cancer cell proliferation, migration and reversing drug resistance. Therefore, the ENPP1 inhibitor can be applied to treatment and prevention of drug resistance and reversing drug resistance, and has efficient clinic application prospects.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular to the application of ENPP1 inhibitors in combination with anticancer drugs in the preparation of antitumor drugs. Background technique [0002] Cancer is one of the major diseases threatening human health worldwide. The latest statistics released by the National Cancer Center in 2019 show that the morbidity and mortality of malignant tumors are still on the rise. Lung cancer, liver cancer, colorectal cancer, and female breast cancer are the main malignant tumors in my country. Lung cancer and breast cancer rank first in the number of male and female cancers, respectively. With the development of molecular diagnostic techniques, it has been discovered that mutations and abnormal expressions of a series of cancer driver genes drive the occurrence and development of tumors. For patients with positive driver genes, molecular targeted therapy can be used, such as EGFR-mutated non-sm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/06A61K31/216A61K33/243A61K31/517A61K31/5377A61K31/506A61P35/00
CPCA61K45/06A61K31/216A61K33/243A61K31/517A61K31/5377A61K31/506A61P35/00A61K2300/00
Inventor 朱亮雷绘敏唐亚斌陈红专张可人吕倩明沈瑛马春爽张雨霏
Owner SHANGHAI JIAOTONG UNIV SCHOOL OF MEDICINE
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