CN111973748A - Application of ENPP1 inhibitor and anticancer drug combined medicine in preparation of antitumor drug - Google Patents

Application of ENPP1 inhibitor and anticancer drug combined medicine in preparation of antitumor drug Download PDF

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CN111973748A
CN111973748A CN202010857037.1A CN202010857037A CN111973748A CN 111973748 A CN111973748 A CN 111973748A CN 202010857037 A CN202010857037 A CN 202010857037A CN 111973748 A CN111973748 A CN 111973748A
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enpp1 inhibitor
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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
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Shanghai Jiaotong University School of Medicine
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Abstract

The invention provides an application of an ENPP1 inhibitor and an anticancer drug in preparation of the anticancer drug, wherein the ENPP1 inhibitor comprises SYL-001 or a siENPP1, shENPP1 and CRISPR-Cas9 preparation delivered by a vector, and the anticancer drug comprises cisplatin, erlotinib, gefitinib or oxitinib. The invention discovers that the ENPP1 inhibitor, a chemotherapeutic drug cisplatin and a lung cancer targeted drug (erlotinib, gefitinib and oxitinib) synergistically play an anti-tumor role, and remarkably inhibits and delays the generation of drug-resistant recurrence phenomena, wherein the cancers comprise colorectal cancer, cervical cancer and lung cancer. More importantly, the ENPP1 inhibitor particularly significantly inhibits the proliferation, migration and reversal of drug resistance of lung cancer cells that have had a relapse after drug resistance. Therefore, the ENPP1 inhibitor can be applied to treatment and prevention of drug resistance and reversal of drug resistance, and has a high-efficiency clinical application prospect.

Description

Application of ENPP1 inhibitor and anticancer drug combined medicine in preparation of antitumor drug
Technical Field
The invention relates to the technical field of medicines, in particular to application of a drug combination of an ENPP1 inhibitor and an anticancer drug in preparation of the antitumor drug.
Background
Cancer is one of the major diseases threatening the global human health. Recent statistics published by the national cancer center in 2019 indicate that the morbidity and mortality of malignant tumors are still on the rising trend. Lung cancer, liver cancer, colorectal cancer, female breast cancer and the like are main malignant tumors in China, and the lung cancer and the breast cancer are the first of the number of people with male cancer and female cancer respectively. With the development of molecular diagnostic techniques, it has been found that the occurrence and development of tumors are driven by the mutation and abnormal expression of a series of cancer-driving genes. Patients who are positive for the driver can use molecular targeted therapy, such as EGFR-mutated non-small cell lung cancer, can use EGFR-TKI to greatly inhibit tumor growth, while patients who are negative for the driver can use traditional chemotherapeutic drugs, such as cisplatin, paclitaxel. Although chemotherapy including molecular targeted therapy can inhibit tumor growth in the early stage of drug administration, a drug resistance phenomenon inevitably occurs, the related scope of the existing drug resistance mechanism is limited, and the drug resistance mechanisms of other layers such as tumor metabolism, epigenetics and the like are still unknown, so that the tumor drug resistance mechanism is urgently needed to be widened from a new idea and dimension, and a drug resistance strategy is supplemented and improved.
ENPP1(Ecto-Nucleotide pyrophosphate/Phosphodiesterase 1, ectonucleotide Pyrophosphatase/Phosphodiesterase 1) is a family of Nucleotide pyrophosphatases that participate in the metabolism of non-classical purines by hydrolyzing various nucleotides such as ATP, GTP, cGAMP, and NAD. ENPP1 has high expression level in bone tissues and cartilage, and the product pyrophosphoric acid (PPi) is mainly involved in hydroxyapatite which is the inorganic component with the highest content in human bone tissues, so at present, international research focuses on ENPP1 for regulating the level of pyrophosphate to promote bone mineralization, soft tissue calcification and the like, but the ENPP1 has no effect on tumor metabolic regulation and tumor drug resistance.
SYL-001 is a commonly used ENPP1 inhibitor with the chemical names (R) -O- (3, 4-dihydroxycinnamoyl) -3- (3, 4-dihydroxyphenyl) lactic acid, 3, 4-dihydroxycinnamic acid (R) -1-carboxy-2- (3, 4-dihydroxyphenyl) ethyl ester, formula: c18H16O8Molecular weight of 360.31, and structural formula as follows:
Figure BDA0002646772060000021
disclosure of Invention
The first purpose of the invention is to provide the application of the ENPP1 inhibitor and the anticancer drug in the preparation of the antitumor drug, wherein the ENPP1 inhibitor can synergistically play the antitumor role of the anticancer drug and delay the occurrence of drug resistance.
The second purpose of the invention is to provide an application of an ENPP1 inhibitor in preparing a medicine for treating drug-resistant recurrent tumors, wherein the inhibition of ENPP1 can inhibit the proliferation capacity of lung cancer cells, and particularly, the proliferation capacity of the lung cancer cells which have been subjected to drug-resistant recurrent tumors is remarkably inhibited.
The third purpose of the invention is to provide a pharmaceutical composition for treating drug-resistant recurrent tumors, wherein the combination of the ENPP1 inhibitor and the chemotherapeutic drug can reverse the drug resistance of the cancer with drug-resistant recurrent tumors to the targeted drug, and can be used for preparing the pharmaceutical composition for treating the drug-resistant recurrent tumors.
In order to achieve the purpose, the invention provides application of an ENPP1 inhibitor and a chemotherapeutic drug in preparation of an antitumor drug, wherein the ENPP1 inhibitor comprises SYL-001 or a vector-delivered siENPP1, shENPP1 and CRISPR-Cas9 preparation, and the chemotherapeutic drug comprises traditional chemotherapeutic drug cisplatin and targeted drug erlotinib, gefitinib or oritinib.
As a preferred embodiment, the tumor is a drug-resistant recurrent tumor, including lung cancer, cervical cancer and colorectal cancer.
In order to achieve the second object, the invention provides application of an ENPP1 inhibitor in preparing a medicine for treating drug-resistant recurrent tumors, wherein the ENPP1 inhibitor comprises SYL-001 or a vector-delivered siENPP1, shENPP1 and CRISPR-Cas9 preparation, and the tumors comprise lung cancer, cervical cancer and colorectal cancer.
In order to achieve the third object, the invention provides a pharmaceutical composition for treating drug-resistant recurrent tumors, which comprises an ENPP1 inhibitor and chemotherapeutic drugs, wherein the ENPP1 inhibitor comprises SYL-001 or vector-delivered siENPP1, shENPP1 and CRISPR-Cas9 preparations, and the chemotherapeutic drugs comprise traditional chemotherapeutic drugs of cisplatin and lung cancer targeted drugs of erlotinib, gefitinib or Hicetinib.
Nucleic acid delivery vehicles in the present invention include, but are not limited to, liposomes, cationic polymers, nanoformulations.
The invention has the advantages that the in vivo experiment of the mouse subcutaneous transplantation tumor model is carried out by using the ENPP1 inhibitor SYL-001, and the experimental result shows that the SYL-001 can inhibit the growth of in vivo tumors, and the in vivo tumor growth can be significantly inhibited by combining with the lung cancer targeted drug of the oxitinib, so that the occurrence of drug resistance is delayed. Further experiments prove that the combined administration of the ENPP1 inhibitor and the chemotherapeutic drug can obviously inhibit the growth of in vivo tumors and can reverse the drug resistance of the lung cancer with drug resistance relapse to the targeted drug. Therefore, the ENPP1 inhibitor can be applied to prevention and reversal of drug resistance, and has a high-efficiency clinical application prospect.
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FIG. 1 shows that siENPP1 inhibits lung cancer cells, especially significantly inhibits migration of drug-resistant cells.
FIG. 2 shows that siENPP1 and an ENPP1 inhibitor SYL-001 inhibit lung cancer cells, particularly significantly inhibit the proliferation of drug-resistant cells.
FIG. 3 shows that siENPP1 and an ENPP1 inhibitor SYL-001 exert a synergistic anti-cancer effect in combination with cisplatin, a cancer chemotherapeutic agent.
FIG. 4 shows that siENPP1 and ENPP1 inhibitor SYL-001 and lung cancer targeted drugs erlotinib, gefitinib and oxitinib are combined to play a synergistic anti-cancer effect.
FIG. 5 shows the effect of combination of siENPP1 and ENPP1 inhibitor SYL-001 with lung cancer targeted drugs erlotinib, gefitinib and oxitinib in reversing drug resistance of lung cancer targeted drug resistant cells.
FIG. 6 shows that the ENPP1 inhibitor SYL-001 can be used alone or in combination with a lung cancer targeted drug oxitinib for inhibiting the growth of tumors in lung cancer cells and delaying the generation of drug resistance.
FIG. 7 shows the effect of SYL-001 inhibitor ENPP1 on the body weight of nude mice in combination with the lung cancer targeting drug oxitinib.
Detailed Description
Hereinafter, the technique of the present invention will be described in detail with reference to specific embodiments. It should be understood that the following detailed description is only for the purpose of assisting those skilled in the art in understanding the present invention, and is not intended to limit the present invention.
Example 1. the effect of siENPP1 in inhibiting lung cancer cells, particularly significantly inhibiting migration of drug-resistant cells of lung cancer, was explored by a transwell experiment, comprising the following specific steps:
(1) collecting recovered and cultured 2-4 generation stably-grown lung cancer and its lung cancer drug-resistant cells, digesting with 0.25% trypsin, preparing single cell suspension with complete culture medium, inoculating into 6-well plate, placing the culture plate at 37 deg.C and 5% CO2And (5) incubating in a constant-temperature cell incubator to enable the cells to grow and adhere to the wall.
(2) Dividing lung cancer and drug-resistant cells thereof into mock group and siENPP1 group, and loading siNC and siENPP1 into corresponding cells respectively after being encapsulated by liposome. Placing the culture plate into an incubator to incubate for 24-48h, digesting with 0.25% trypsin,preparing single cell suspension with serum-free basic culture medium, and adjusting cell density to 5 × 105one/mL.
(3) Adding 500 μ L complete culture medium into lower chamber of 24-well plate, collecting cell suspension 100 μ L, adding into upper chamber, placing culture plate at 37 deg.C and 5% CO2Incubation was carried out in a thermostatted cell incubator for 16 h.
(4) The medium in the upper and lower chambers was aspirated, and 500. mu.L of PBS was added to the upper and lower chambers, respectively, and washed 2 times.
(5) Add 500. mu.L of 4% paraformaldehyde to the lower chamber and fix for 15 min.
(6) The upper and lower chambers were blotted with 4% paraformaldehyde, and 500. mu.L of PBS was added to the upper and lower chambers, respectively, and washed 2 times.
(7) Add 500. mu.L of 0.1% crystal violet to the lower chamber and stain for 1 h.
(8) The crystal violet was recovered from the upper and lower chambers, and 500 μ L PBS was added to the upper and lower chambers, respectively, and washed 2 times, and the cells in the upper chamber were gently wiped off with a cotton swab.
(9) Under an upright microscope, 5 fields were randomly selected for photographing.
(10) The PBS in the upper and lower chambers was aspirated, 10% glacial acetic acid was added to the upper chamber, and the mixture was allowed to stand for 10 min.
(11) Glacial acetic acid was pipetted into a 96-well plate and the absorbance was measured at 600 nm.
(12) Relative mobility ═ ODtreated/ODcontrol×100%。
The results are shown in fig. 1, and the siENPP1 can inhibit the migration of lung cancer cells, and has more obvious inhibition effect on lung cancer drug-resistant cells. The invention also discloses that the inhibition of ENPP1 can inhibit the migration of lung cancer cells, particularly drug-resistant cells for the first time.
Example 2 inhibition of Lung cancer cells, particularly significant inhibition of proliferation of drug resistant cells, by sENPP 1 and ENPP1 inhibitor SYL-001
The method comprises the following specific steps:
(1) taking recovered and cultured lung cancer and drug-resistant cells thereof with 2-4 generations stable growth, preparing single cell suspension, inoculating the single cell suspension into a 96-well plate, placing the plate in a 37 ℃ and 5% CO2 incubator to enable the plate to grow and adhere to the wall.
(2) siENPP 1: under microscope observation, the cell confluence degree reaches about 40-60%, and the lung cancer and drug-resistant cells thereof are divided into mock group and siENPP1 group. The siNC and the siENPP1 were encapsulated by liposomes and then added to the corresponding cells, and the culture plate was placed in an Incucyte viable cell detector for real-time monitoring for 72 h.
(3) SYL-001: dividing lung cancer and drug-resistant cells thereof into a DMSO group and a SYL-001 group, respectively adding drugs and solvent control into corresponding cells, and putting the culture plate into an Incucyte living cell detector for real-time monitoring for 72 h.
The results are shown in fig. 2, the siENPP1 and the ENPP1 inhibitor SYL-001 can inhibit the proliferation of lung cancer cells, particularly the proliferation capacity of lung cancer drug-resistant cells is obviously inhibited, and the invention also discovers for the first time that the inhibition of ENPP1 can obviously inhibit the proliferation of lung cancer and the drug-resistant cells thereof.
Example 3 combination of the siENPP1 and ENPP1 inhibitors SYL-001 with cisplatin as a cancer chemotherapeutic agent for synergistic anti-cancer effects
The method comprises the following specific steps:
(1) culturing lung cancer, breast cancer, cervical cancer and colorectal cancer cells which grow stably for 2-4 generations after recovery to prepare single cell suspension, inoculating the single cell suspension into a 96-well plate, placing the single cell suspension into a 5% CO2 incubator at 37 ℃ to ensure that the single cell suspension grows to adhere to the wall.
(2) Observing the cell confluence degree to be about 40-60% under a microscope, and respectively setting the tumor cells into a DMSO group, a chemotherapeutic drug group cisplatin, a siENPP1 group, a SYL-001 group, a chemotherapeutic drug group + siENPP group and a chemotherapeutic drug group + SYL-001 group. Drugs or siRNA were added to the corresponding cells, respectively, and the plates were placed in an Incucyte viable cell detector for real-time monitoring for 72 h.
(3) After the drug acts for 72 hours, old culture solution in the culture plate is sucked, CCK-8 is diluted by complete culture solution according to the proportion of 1:10, and 100 mu L of newly prepared CCK-8 working solution is added into each hole.
(4) The plates were incubated at 37 ℃ in 5% CO2Incubating for 0.5-2h in a constant-temperature cell incubator, and measuring the absorbance at 450nm by using an enzyme-labeling instrument.
The results are shown in FIG. 3, where the combination of the siENPP1 and ENPP1 inhibitor SYL-001 with cisplatin, a conventional chemotherapeutic drug, showed synergistic anti-cancer effects.
Example 4 combination of the siENPP1 and ENPP1 inhibitors SYL-001 with lung cancer targeting drugs erlotinib, gefitinib and oxitinib to exert synergistic anticancer effects
The method comprises the following specific steps:
(1) collecting recovered lung cancer cells cultured for 2-4 generations, preparing single cell suspension, inoculating into 96-well plate with cell density of 3000 cells/well, placing at 37 deg.C and 5% CO2And (5) an incubator for enabling the growth to adhere to the wall.
(2) Observing the cell confluence degree to be about 40-60% under a microscope, and respectively setting the tumor cells into a DMSO group, a lung cancer targeted drug group (erlotinib, gefitinib and oxitinib), a siENPP1 group, a SYL-001 group, a lung cancer targeted drug group + siENPP group and a lung cancer targeted drug group + SYL-001 group. Drugs or siRNA were added to the corresponding cells, respectively, and the plates were placed in an Incucyte viable cell detector for real-time monitoring for 72 h.
(3) After the drug acts for 72 hours, old culture solution in the culture plate is sucked, CCK-8 is diluted by complete culture solution according to the proportion of 1:10, and 100 mu L of newly prepared CCK-8 working solution is added into each hole.
(4) The plates were incubated at 37 ℃ in 5% CO2Incubating for 0.5-2h in a constant-temperature cell incubator, and measuring the absorbance at 450nm by using an enzyme-labeling instrument.
The results are shown in fig. 4, and the combination of siENPP1 and an ENPP1 inhibitor SYL-001 and lung cancer targeted drugs erlotinib, gefitinib or oxitinib can play a role in synergistic treatment of lung cancer.
Example 5 Effect of combination of sENPP 1 and ENPP1 inhibitor SYL-001 with Lung cancer-targeting drugs erlotinib, Gefitinib and Olicetinib on reversing drug-resistant cell-targeting drug resistance in Lung cancer
The method comprises the following specific steps:
(1) taking recovered lung cancer drug-resistant cells cultured for 2-4 generations to prepare single cell suspension, inoculating the single cell suspension into a 96-well plate, placing the plate in a culture box with the cell density of 3000 cells/hole and 5% CO2 at 37 ℃ to ensure that the cells grow and adhere to the wall.
(2) Observing the cell confluence degree to be about 40-60% under a microscope, and respectively setting the tumor cells into a DMSO group, a lung cancer targeted drug group (erlotinib, gefitinib and oxitinib), a siENPP1 group, a SYL-001 group, a lung cancer targeted drug group + siENPP group and a lung cancer targeted drug group + SYL-001 group. Drugs or siRNA were added to the corresponding cells, respectively, and the plates were placed in an Incucyte viable cell detector for real-time monitoring for 72 h.
(3) After the drug acts for 72 hours, old culture solution in the culture plate is sucked, CCK-8 is diluted by complete culture solution according to the proportion of 1:10, and 100 mu L of newly prepared CCK-8 working solution is added into each hole.
(4) The plates were incubated at 37 ℃ in 5% CO2Incubating for 0.5-2h in a constant-temperature cell incubator, and measuring the absorbance at 450nm by using an enzyme-labeling instrument.
The results are shown in fig. 5, and the combination of siENPP1 and an ENPP1 inhibitor SYL-001 and lung cancer targeted drugs erlotinib, gefitinib or oxitinib can reverse the effect of lung cancer drug-resistant cells on targeted drug resistance.
Example 6 inhibition of tumor growth and delay of drug resistance in Lung cancer cells by ENPP1 inhibitor SYL-001 alone or in combination with Lung cancer targeting drug Oxitinib
The SPF-grade BALB/c immune defect type nude mice used in the experiment are 3-4 weeks old and female, and are provided by Shanghai Sphere-BiKai laboratory animals Co., Ltd, and the animal experiment operation meets the requirements of 'laboratory animal management regulations'.
The specific steps of establishing a nude mouse subcutaneous xenograft tumor model are as follows: expanding lung cancer cells, resuspending the cells and making into the density of 2-3 × 107 Inoculating 100 μ L lung cancer cells to axilla of upper limb of nude mouse with thymus immunodeficiency, and allowing the tumor volume to be 200mm3On the left and right, nude mice were randomly divided into 4 groups, which were a solvent control group, an oxitinib group, a SYL-001 group, and an oxitinib + SYL-001 combination administration group. All the medicines are administrated by intragastric administration. The tumor of the control group grows to 1500mm3The nude mice were euthanized, the subcutaneous graft tumors were removed, photographed and weighed.
The result is shown in fig. 6, the ENPP1 inhibitor SYL-001 can obviously inhibit the growth of the lung cancer subcutaneous transplanted tumor and delay the generation of the drug resistance of the Oxitinib by using the single or combined lung cancer targeted drug Oxitinib.
The weights of the mice were weighed every other day in the experiment, the weight changes are shown in fig. 7, and no obvious difference exists among the weights of the mice in the solvent control group, the oxitinib group, the SYL-001 group and the oxitinib + SYL-001 combined administration group, which indicates that the SYL-001 has good treatment effect and low toxic and side effects.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (4)

  1. The application of the ENPP1 inhibitor and an anticancer drug in preparation of the antitumor drug is characterized in that the ENPP1 inhibitor comprises SYL-001 or a vector-delivered siENPP1, shENPP1 and CRISPR-Cas9 preparation, and the anticancer drug comprises traditional chemotherapeutic drug cisplatin and targeted drug erlotinib, gefitinib or oxitinib.
  2. 2. The use of an ENPP1 inhibitor in combination with an anticancer agent for the preparation of an antitumor medicament according to claim 1, wherein said tumor comprises lung cancer, cervical cancer and colorectal cancer.
  3. The application of the ENPP1 inhibitor in preparing the medicine for treating the drug-resistant recurrent tumor is characterized in that the ENPP1 inhibitor comprises SYL-001 or a vector-delivered siENPP1, shENPP1 and CRISPR-Cas9 preparation, and the tumor is the drug-resistant recurrent tumor comprising lung cancer, cervical cancer and colorectal cancer.
  4. 4. A pharmaceutical composition for treating drug-resistant recurrent tumors, which comprises an ENPP1 inhibitor and chemotherapeutic drugs, wherein the ENPP1 inhibitor comprises SYL-001 or a vector-delivered siENPP1, shENPP1 and CRISPR-Cas9 preparation, and the anticancer drugs comprise a traditional chemotherapeutic drug cis-platinum and a targeted drug erlotinib, gefitinib or oxitinib.
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CN114767863B (en) * 2022-04-29 2024-01-30 西北工业大学 Application of ENPP2 gene or protein in regulation and control of colorectal cancer cells
CN115381836A (en) * 2022-09-30 2022-11-25 上海纳米技术及应用国家工程研究中心有限公司 Combination drug for treating lung cancer

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