CN115317487B - Pharmaceutical composition containing 5-bromo tetrandrine ethyl formate and PARP-1 inhibitor - Google Patents
Pharmaceutical composition containing 5-bromo tetrandrine ethyl formate and PARP-1 inhibitor Download PDFInfo
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 26
- 239000003112 inhibitor Substances 0.000 title claims abstract description 24
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- 206010064571 Gene mutation Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
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- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
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- HMABYWSNWIZPAG-UHFFFAOYSA-N rucaparib Chemical compound C1=CC(CNC)=CC=C1C(N1)=C2CCNC(=O)C3=C2C1=CC(F)=C3 HMABYWSNWIZPAG-UHFFFAOYSA-N 0.000 description 1
- 229950004707 rucaparib Drugs 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4748—Quinolines; Isoquinolines forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Reproductive Health (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a pharmaceutical composition containing 5-bromotetrandrine ethyl formate (W17) and a poly (adenosine diphosphate) ribose polymerase-1 (PARP-1) inhibitor, and application thereof in preparing medicines for treating drug-resistant ovarian cancer, in particular to a pharmaceutical composition containing 5-bromotetrandrine ethyl formate (W17) and olaparib and nilaparib, which has synergistic sensitization and drug-resistant reversal effects and can remarkably improve the curative effect of treating drug-resistant ovarian cancer.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a pharmaceutical composition containing 5-bromo tetrandrine ethyl formate (W17) and a poly (adenosine diphosphate) -ribose polymerase-1 (PARP-1) inhibitor, and application thereof in medicines for treating drug-resistant ovarian cancer, in particular to a pharmaceutical composition containing 5-bromo tetrandrine ethyl formate (W17) and olaparib and nilaparib, and application thereof in preparation of medicines for treating drug-resistant ovarian cancer.
Background
Malignant tumors are the most lethal of all diseases at present. 29.5 ten thousand ovarian Cancer patients are newly increased worldwide in 2018, 18.5 ten thousand ovarian cancers die, the incidence and mortality rate of which are eighth among all cancers in women, and are one of three common Cancer types in women (Bray F et al, CA Cancer J Clin,2018, 68:394-424.).
In ovarian cancer mutated by the oncogene BRCA, the homologous recombination repair function is damaged, and the DNA double-strand break repair function of tumor cells is damaged, so that the DNA repair pathway depends on the repair of the DNA single-strand break mediated by the poly (A-ribose) polymerase-1 (PARP-1) to maintain the survival of the DNA. Thus, the simultaneous action of PARP-1 inhibitors and BRCA gene mutation can further aggravate DNA damage, so that cellular DNA cannot be repaired recombinantly to die, which is a "synthetic lethal" effect. PARP-1 inhibitors such as olaparib, lu Kapa b, nilaparib, tazopanib or fluzopanib act through synthetic lethal effects. There are a number of PARP-1 inhibitors currently approved for sale or in clinical research. Olaparib (structural formula shown below) was developed by AstraZeneca corporation, approved by the FDA for marketing in 2014, and was the first approved marketing oral PARP-1 inhibitor, and was the first approved PARP-1 inhibitor for the first line maintenance therapy of BRCA mutant ovarian cancer. Nilapatinib (structural formula shown below) is researched and developed by Merck Sharp and Dohme together with Tesaro, is approved by FDA to be marketed in 2017, is a PARP-1 inhibitor which can be used for detection without BRCA mutation or other biomarkers, and is more widely applicable to people. However, with the wide application of olaparib, nilaparib and the like in clinic, part of ovarian cancer patients have drug resistance to treatment of PARP-1 inhibitors due to a plurality of mechanism factors, such as secondary mutation of BRCAl/2 and the like, which seriously affects the long-term use and curative effect in clinic.
The dibenzyl isoquinoline alkaloid Tetrandrine (Tetrandrine) is the main active ingredient of root of radix Stephaniae Tetrandrae of Menispermaceae, and can be used for treating rheumatalgia, arthralgia, neuralgia, malignant tumor, silicosis, etc. Studies have shown that tetrandrine and its derivatives can enhance the sensitivity of chemotherapeutic drugs to resistant tumors by a variety of mechanisms (Wang G et al, life Sci,1995,56 (5): 295-06; liu XD et al, cancer Lett,2010, 292 (1): 24-31; wei N et al, cancer Chemother Pharmacol,2011, 67 (5): 1017-25.). The inventor modifies the structure of tetrandrine to obtain novel tetrandrine derivative 5-bromotetrandrine ethyl formate (W17, the structural formula is shown as below), and preliminary researches show that the combination of W17 and PARP-1 inhibitor has excellent in vitro tumor multidrug resistance reversal activity and synergistic sensitization.
Disclosure of Invention
The invention aims to provide an application of a combined drug or composition of 5-bromo tetrandrine formate (W17) and a poly (adenosine diphosphate) ribose polymerase-1 (PARP-1) inhibitor in treating tumors, in particular to tumors with drug resistance. Shows excellent in vitro tumor multidrug resistance reversal activity and synergistic sensitization.
To achieve the object of the present invention, the following embodiments are provided.
The invention discloses an anti-tumor pharmaceutical composition, which is characterized in that: comprises ethyl 5-bromotetrandrine formate (W17) and a poly (adenosine diphosphate) ribose polymerase-1 (PARP-1) inhibitor.
Preferably, the above pharmaceutical composition of the present invention, the poly (adenosine diphosphate) ribose polymerase-1 (PARP-1) inhibitor is selected from the group consisting of olaparib, lu Kapa, nilaparib, tazopanib and fluzopanib, more preferably olaparib or nilaparib.
Preferably, the molar ratio of the 5-bromo tetrandrine ethyl formate to the olaparib or the nilaparib in the pharmaceutical composition of the present invention is (0.50-3.0): (10-100).
Preferably, in the above pharmaceutical composition of the present invention, the tumor is ovarian cancer, preferably drug-resistant ovarian cancer.
In some embodiments, the pharmaceutical composition of the present invention further comprises pharmaceutically acceptable pharmaceutical excipients, and the preparation form of the pharmaceutical composition is oral tablet, granule, capsule or injection.
In another embodiment, there is provided the use of ethyl 5-bromo-tetrandrine formate (W17) in the manufacture of a medicament for the treatment of a drug resistant tumor, said use comprising co-administering or composing W17 with olaparib, lu Kapa ni, nilaparib, tazopanib and fluzopanib in a fixed dose pharmaceutical composition.
Preferably, for the above use of the present invention, the resistant tumor is resistant ovarian cancer.
Preferably, the use of the invention as described above comprises the combination of W17 with olaparib or nilaparib or the composition of a fixed dose pharmaceutical composition.
The inventors found that ethyl 5-bromotetrandrine formate (also referred to herein as "W17") had no antitumor activity at low concentrations, e.g., 0.50. Mu.M to 3.0. Mu.M alone, but as a result of further intensive studies, it was unexpectedly found that the W17 compound could significantly enhance antitumor activity by inhibiting the drug efflux protein Pgp, affecting tumor apoptosis and survival proliferation signaling pathways, when used in combination with an adenosine diphosphate ribose polymerase-1 (PARP-1) inhibitor, such as Olaparib, nilapatinib (10. Mu.M to 100. Mu.M).
The above pharmaceutical composition or use of the present invention, the PARP-1 inhibitor is selected from the group consisting of olaparib (olaparib), lu Kapa ni (rucaparib), nilaparib (nirapparib), tazopanib (tazopanib) and fluzopanib (fluzopanib).
The pharmaceutical composition of the present invention, wherein the molar ratio of 5-bromotetrandrine ethyl formate (W17) to PARP-1 inhibitor is (0.50-3.0): (10-100).
The pharmaceutical composition of the invention is in the form of oral tablets, granules, capsules and injections.
The pharmaceutical composition of the invention also comprises pharmaceutically acceptable pharmaceutical excipients.
The pharmaceutical composition of the invention is prepared from the pharmaceutical excipients commonly used in the field, fillers such as calcium hydrophosphate, starch, microcrystalline cellulose, ethylcellulose, mannitol, lactose and the like, disintegrating agents such as pregelatinized starch, sodium carboxymethyl starch, crosslinked sodium carboxymethyl cellulose, crosslinked povidone, binders such as low-substituted hydroxypropyl cellulose, ethanol, water, povidone and the like, and lubricants such as talcum powder, magnesium stearate and the like.
The invention also provides an application of the 5-bromo tetrandrine ethyl formate (W17) and the PARP-1 inhibitor in preparing medicines for treating drug-resistant ovarian cancer, wherein the PARP-1 inhibitor is preferably selected from the group consisting of Olaparib and Nilapatinib.
When the 5-bromo tetrandrine ethyl formate (W17) and the PARP-1 inhibitor, such as Olaparib and Nilapatinib, are used together, obvious synergistic sensitization is generated, the anti-tumor activity of the PARP-1 inhibitor is obviously enhanced, and the synergistic sensitization to drug-resistant ovarian cancer cells is particularly outstanding.
Detailed Description
The following examples are provided to further understand the synergistic effect of the present invention and should not be taken to limit the scope of the invention.
Example 1
Synergistic sensitization of anti-proliferative activity of OVCAR5 cells of intrinsically resistant ovarian cancer with the combination of W17 and olaparib.
The MTT assay detects the effect of olaparib alone or in combination with W17 on the antiproliferative effect of intrinsically resistant ovarian cancer OVCAR5 cells.
MTT assay to detect antiproliferative activity of olaparib alone or in combination with W17 on intrinsically resistant ovarian cancer OVCAR5 cells: 3000 cells/hole of OVCAR5 cells in logarithmic phase are inoculated into a 96-hole culture plate, after overnight culture adherence, the Olaparib (10-100 mu M) with gradient concentration or W17 (0.50-3.0 mu M) or the combination of the two medicines is added, and each medicine concentration is set3 parallel holes. After further culturing for 72 hours, the culture broth was discarded, 100. Mu.l of MTT (serum-free RPMI1640 culture broth was dissolved) was added to each well, and after further culturing for 4 hours, 150. Mu.l of DMSO was added to each well, and absorbance was measured at a wavelength of 5min and 570nm by mixing and shaking, and antiproliferative activity (inhibition ratio) was calculated by the following formula: inhibition (%) = (OD mean of 1-drug treated cells/OD mean of control cells) ×100%, three independent experiments were expressed as mean ± SD, ×p<0.05，**P<0.01vs. Olaparib (10. Mu.M); # P<0.05， ## P<0.01vs. Olaparib (25. Mu.M); △ P<0.05, △△ P<0.01vs. Olaparib (50. Mu.M); ▽ P<0.05vs. Olaparib (100. Mu.M).
The results are shown in Table 1, the anti-proliferation activity of Olaparib (10-100 mu M) on OVCAR5 cells is poor when the Olaparib is singly acted, and the anti-proliferation activity of the OVCAR5 cells is obviously enhanced after the Olaparib is combined with low concentration W17 (0.50-3.0 mu M), so that the Olaparib has obvious synergistic effect.
TABLE 1 influence of W17 in combination with Olaparib on the antiproliferative activity of intrinsically resistant ovarian cancer OVCAR5 cells
Example 2
Synergistic sensitization of anti-proliferative activity of an internally resistant ovarian cancer OVCAR5 cell with the combination of W17 and nilaparib.
The MTT method detects the effect of single or combined use of Nilapatinib on the anti-proliferation effect of the internal drug-resistant ovarian cancer OVCAR5 cells, as shown in the results of table 2, the anti-proliferation activity of Nilapatinib (10-100 mu M) on the OVCAR5 cells is poor when the single use or combined use of the Nilapatinib and the combined use of the low concentration W17 (0.50-3.0 mu M), the anti-proliferation activity of the Nilapatinib on the OVCAR5 cells is obviously enhanced, and the anti-proliferation effect of the Nilapatinib on the OVCAR5 cells is obvious in synergy.
TABLE 2 influence of W17 in combination with Nilapatinib on the antiproliferative activity of intrinsically resistant ovarian cancer OVCAR5 cells
Note that: MTT assay for anti-proliferative Activity of Nilapatinib alone or in combination with W17 on inherently resistant ovarian carcinoma OVCAR5 cells (same as example 1), table 2, P<0.01vs. nilaparib (10. Mu.M); # P<0.05， ## P<0.01vs. nilaparib (25. Mu.M); △ P<0.05vs. nilaparib (50. Mu.M); ▽ P<0.05vs. Nilapatinib (100. Mu.M).
Example 3
Synergistic sensitization of acquired drug-resistant ovarian cancer A2780/R cells to antiproliferative activity with the combination of W17 and Olaparib.
The MTT assay detects the antiproliferative activity of Olaparib alone or in combination with W17 on acquired drug resistant ovarian cancer A2780/R cells: 5000 cells/hole logarithmic phase A2780/R cells are inoculated into a 96-hole culture plate, after overnight culture adherence, the Olaparib (10-100 mu M) with gradient concentration, or W17 (0.50-3.0 mu M) or the combination of the two medicines is added, and each medicine concentration is provided with 3 parallel holes. After further culturing for 72 hours, the culture broth was discarded, 100. Mu.l of MTT (serum-free RPMI1640 culture broth was dissolved) was added to each well, and after further culturing for 4 hours, 150. Mu.l of DMSO was added to each well, and absorbance was measured at a wavelength of 5min and 570nm by mixing and shaking, and antiproliferative activity (inhibition ratio) was calculated by the following formula: inhibition (%) = (OD mean of 1-drug treated cells/OD mean of control cells) ×100%, three independent experiments were expressed as mean ± SD, ×p<0.05，**P<0.01vs. Olaparib (10. Mu.M); # P<0.05， ## P<0.01vs. Olaparib (25. Mu.M); △ P<0.05, △△ P<0.01vs. Olaparib (50. Mu.M); ▽ P<0.05vs. Olaparib (100. Mu.M).
The MTT method detects the influence of single or combined W17 of Olaparib on the antiproliferative activity of the obtained drug-resistant ovarian cancer A2780/R cells, and the result is shown in a table 3, wherein the antiproliferative activity of Olaparib (10-100 mu M) on the A2780/R cells is poor when the Olaparib is singly acted, and the antiproliferative activity of the Olaparib on the A2780/R cells is obviously enhanced after the Olaparib is combined with low-concentration W17 (0.50-3.0 mu M), so that the Olaparib has obvious synergistic effect.
TABLE 3 influence of W17 combination of Olaparib on the antiproliferative Activity of acquired drug-resistant ovarian cancer A2780/R cells
Example 4
Synergistic sensitization of acquired drug-resistant ovarian cancer A2780/R cells to antiproliferative activity with Nilapatinib in combination with W17.
MTT method detects the effect of single or combined use of Nilapatinib on the antiproliferative effect of acquired drug-resistant ovarian cancer A2780/R cells, as shown in Table 4, when Nilapatinib (10-100 mu M) acts alone, the antiproliferative activity on A2780/R cells is poor, and when combined with low concentration of W17 (0.50-3.0 mu M), the antiproliferative activity on A2780/R cells is obviously enhanced, and the obvious synergistic effect is achieved.
TABLE 4 influence of W17 combination of Nilapatinib on antiproliferative Activity of acquired drug-resistant ovarian cancer A2780/R cells
Note that: the MTT assay detects the antiproliferative activity of Nilapatinib alone or in combination with W17 on acquired drug resistant ovarian cancer A2780/R cells (as in example 3): in table 4, P<0.05，**P<0.01vs. nilaparib (10. Mu.M); # P<0.05， ## P<0.01vs. nilaparib (25. Mu.M); △ P<0.05vs. nilaparib (50. Mu.M); ▽ P<0.05vs. Nilapatinib (100. Mu.M).
Example 5
Synergistic inhibition of single cell proliferation and clonality of OVCAR5 cells of intrinsically resistant ovarian cancer by the combination of W17 and olaparib.
Colony formation experiments to examine the effect of olaparib alone or in combination with W17 on the single cell proliferation and clonality of an intrinsically resistant ovarian cancer OVCAR5 cell: diluting the suspension of OVCAR5 cells in exponential growth phase by multiple ratio, and respectively inoculating 5 according to the concentration of 200 cells in each dishml of the cell suspension was placed in a dish (diameter: 60 mm), and the dish was gently shaken in a cross direction to disperse the cells uniformly. Placing the culture dish at 37 ℃ and 5% CO 2 After culturing for 24h, the cells are attached, the Olaparib (10-100 mu M) with gradient concentration, or W17 (0.50-3.0 mu M) or the combination of the two medicines is added, the culture solution is discarded, the PBS solution is carefully soaked for 2 times, and the air is dried. The methanol was fixed for 15min, and air dried after discarding the methanol. Dyeing with Giemsa dye liquor for 10min, washing off the dye liquor slowly with running water, and air drying. The colony formation rate was calculated by counting more than 50 cell clones under a microscope as follows: colony formation rate (%) = (colony number/number of inoculated cells) ×100%, and results of three independent experiments are expressed as mean ± SD, P ×<0.05，**P<0.01vs. Olaparib (10. Mu.M); # P<0.05， ## P<0.01vs. Olaparib (25. Mu.M); △ P<0.05, △△ P<0.01vs. Olaparib (50. Mu.M); ▽ P<0.05， ▽▽ P<0.01vs. Olaparib (100. Mu.M).
Colony formation experiments detect the influence of single-use or combined use of the W17 on single-cell proliferation and clonality of the OVCAR5 cells of the inherent drug-resistant ovarian cancer, and the result is shown in a table 5, the single-use or combined use of the W17 with low concentration (0.50-3.0 mu M) has no obvious influence on the single-cell proliferation and clonality (colony formation rate%) of the OVCAR5 cells, but obviously enhances the inhibition effect on the colony formation of the OVCAR5 cells after combined use of the Olaparib (10-100 mu M), and has a synergistic effect.
TABLE 5 influence of W17 in combination with Olaparib on OVCAR5 cell colony Forming Rate (%)
Example 6
Synergistic inhibition of the single cell proliferation and clonality of OVCAR5 cells of an inherently resistant ovarian cancer by the combination of W17 and nilaparib.
Colony formation assay to examine the effect of Nilapatinib alone or in combination with W17 on the single cell proliferation and clonality of an internal drug-resistant ovarian cancer OVCAR5 cell, the assay was performed as described in example 5, knotsAs shown in table 6, the single action of low concentration W17 (0.50-3.0 μm) has no obvious effect on the single cell proliferation and the clonality (colony forming rate%) of OVCAR5 cells, but the inhibition effect on the colony formation of OVCAR5 cells is obviously enhanced after being combined with nilaparib (10-100 μm), and the synergism is achieved. In table 6, P<0.05，**P<0.01vs. nilaparib (10. Mu.M); # P<0.05， ## P<0.01vs. nilaparib (25. Mu.M); △ P<0.05， △△ P<0.01vs. nilaparib (50. Mu.M); ▽ P<0.05， ▽▽ P<0.01vs. nilaparib (100. Mu.M).
TABLE 6 influence of W17 in combination with Nilapatinib on OVCAR5 cell colony formation (%)
Example 7
Synergistic inhibition of single cell proliferation and clonality of acquired drug-resistant ovarian cancer A2780/R cells by combination of W17 and Olaparib.
Colony formation experiments detect the influence of single-use or combined use of Olaparib on single-cell proliferation and clonality of acquired drug-resistant ovarian cancer A2780/R cells, the method is the same as that of example 5, and the result is shown in Table 7, the single effect of low concentration W17 (0.50-3.0 mu M) has no obvious influence on single-cell proliferation and clonality (colony formation rate%) of A2780/R cells, but the combined use of Olaparib (10-100 mu M) obviously enhances the inhibition effect on the colony formation of A2780/R cells, and has a synergistic effect. In table 7, P<0.05，**P<0.01vs. Olaparib (10. Mu.M); # P<0.05， ## P<0.01vs. Olaparib (25. Mu.M); △ P<0.05, △△ P<0.01vs. Olaparib (50. Mu.M); ▽ P<0.05， ▽▽ P<0.01vs. Olaparib (100. Mu.M).
TABLE 7 influence of W17 in combination with Olaparib on A2780/R cell colony formation (%)
Example 8
Synergistic inhibition of single cell proliferation and clonality of acquired drug-resistant ovarian cancer A2780/R cells by combination of W17 and nilaparib.
Colony formation experiments detect the influence of single use or combined use of the W17 on single cell proliferation and clonality of the acquired drug-resistant ovarian cancer A2780/R cells, the experimental method is the same as that of example 5, and the result is shown in the table 5, the single effect of the low concentration W17 (0.50-3.0 mu M) has no obvious influence on the single cell proliferation and clonality (colony formation rate%) of the A2780/R cells, but obviously enhances the inhibition effect on the colony formation of the A2780/R cells after combined use of the single use or combined use of the W17 and the combined use of the single use of the N-type W17 and the combined use of the N-type W17 and the N-type W-R cells, and has a synergistic effect. In table 8, P<0.05，**P<0.01vs. nilaparib (10. Mu.M); # P<0.05， ## P<0.01vs. nilaparib (25. Mu.M); △ P<0.05， △△ P<0.01vs. nilaparib (50. Mu.M); ▽ P<0.05， ▽▽ P<0.01vs. nilaparib (100. Mu.M).
TABLE 8 influence of the combination of W17 and Nilapatinib on the A2780/R cell colony formation (%)
Claims (8)
1. An anti-tumor pharmaceutical composition is characterized by comprising 5-bromotetrandrine ethyl formate and a poly (adenosine diphosphate) ribose polymerase-1 inhibitor, wherein the poly (adenosine diphosphate) ribose polymerase-1 inhibitor is olaparib or nilaparib, and the structural formula of the 5-bromotetrandrine ethyl formate is as follows:。
2. the pharmaceutical composition according to claim 1, wherein the molar ratio of 5-bromotetrandrine ethyl formate to olaparib, nilaparib is (0.50-3.0): (10-100).
3. The pharmaceutical composition of claim 1, wherein the tumor is ovarian cancer.
4. The pharmaceutical composition of claim 3, wherein the ovarian cancer is drug resistant ovarian cancer.
5. The pharmaceutical composition according to any one of claims 1-4, further comprising a pharmaceutically acceptable pharmaceutical excipient.
6. The pharmaceutical composition according to claim 5, which is in the form of an oral tablet, granule, capsule or injection.
7. The application of a pharmaceutical composition of 5-bromo tetrandrine ethyl formate and Olaparib or Nilaparib combined drug or a composition fixing agent in preparing a drug for treating drug-resistant tumor is provided, wherein the structural formula of the 5-bromo tetrandrine ethyl formate is as follows:
。
8. the use of claim 7, wherein the resistant tumor is resistant ovarian cancer.
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