CN115364228A - Pharmaceutical composition for treating ovarian cancer - Google Patents
Pharmaceutical composition for treating ovarian cancer Download PDFInfo
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- CN115364228A CN115364228A CN202211142307.6A CN202211142307A CN115364228A CN 115364228 A CN115364228 A CN 115364228A CN 202211142307 A CN202211142307 A CN 202211142307A CN 115364228 A CN115364228 A CN 115364228A
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- pharmaceutical composition
- oleanolic acid
- cancer
- ovarian cancer
- parp inhibitor
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- 206010033128 Ovarian cancer Diseases 0.000 title claims abstract description 26
- 206010061535 Ovarian neoplasm Diseases 0.000 title claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 16
- MIJYXULNPSFWEK-GTOFXWBISA-N 3beta-hydroxyolean-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C MIJYXULNPSFWEK-GTOFXWBISA-N 0.000 claims abstract description 40
- JKLISIRFYWXLQG-UHFFFAOYSA-N Epioleonolsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4CCC3C21C JKLISIRFYWXLQG-UHFFFAOYSA-N 0.000 claims abstract description 40
- YBRJHZPWOMJYKQ-UHFFFAOYSA-N Oleanolic acid Natural products CC1(C)CC2C3=CCC4C5(C)CCC(O)C(C)(C)C5CCC4(C)C3(C)CCC2(C1)C(=O)O YBRJHZPWOMJYKQ-UHFFFAOYSA-N 0.000 claims abstract description 40
- MIJYXULNPSFWEK-UHFFFAOYSA-N Oleanolinsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4=CCC3C21C MIJYXULNPSFWEK-UHFFFAOYSA-N 0.000 claims abstract description 40
- 229940100243 oleanolic acid Drugs 0.000 claims abstract description 40
- HZLWUYJLOIAQFC-UHFFFAOYSA-N prosapogenin PS-A Natural products C12CC(C)(C)CCC2(C(O)=O)CCC(C2(CCC3C4(C)C)C)(C)C1=CCC2C3(C)CCC4OC1OCC(O)C(O)C1O HZLWUYJLOIAQFC-UHFFFAOYSA-N 0.000 claims abstract description 40
- 239000003814 drug Substances 0.000 claims abstract description 30
- 239000012661 PARP inhibitor Substances 0.000 claims abstract description 25
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- FAQDUNYVKQKNLD-UHFFFAOYSA-N olaparib Chemical group FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 claims description 8
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- HWGQMRYQVZSGDQ-HZPDHXFCSA-N chembl3137320 Chemical compound CN1N=CN=C1[C@H]([C@H](N1)C=2C=CC(F)=CC=2)C2=NNC(=O)C3=C2C1=CC(F)=C3 HWGQMRYQVZSGDQ-HZPDHXFCSA-N 0.000 claims description 3
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- DENYZIUJOTUUNY-MRXNPFEDSA-N (2R)-14-fluoro-2-methyl-6,9,10,19-tetrazapentacyclo[14.2.1.02,6.08,18.012,17]nonadeca-1(18),8,12(17),13,15-pentaen-11-one Chemical compound FC=1C=C2C=3C=4C(CN5[C@@](C4NC3C1)(CCC5)C)=NNC2=O DENYZIUJOTUUNY-MRXNPFEDSA-N 0.000 claims description 2
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- PCHKPVIQAHNQLW-CQSZACIVSA-N niraparib Chemical compound N1=C2C(C(=O)N)=CC=CC2=CN1C(C=C1)=CC=C1[C@@H]1CCCNC1 PCHKPVIQAHNQLW-CQSZACIVSA-N 0.000 claims 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
- 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
- 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
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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- 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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Abstract
The invention relates to an application of a pharmaceutical composition in preparing an anti-tumor medicament. The pharmaceutical composition comprises the application of oleanolic acid and a PARP inhibitor in combination therapy of ovarian cancer. Compared with a single medicine, the oleanolic acid and the PARP inhibitor are combined to further enhance the anti-tumor effect, generate obvious synergistic effect and can be used for effectively killing tumor cells such as ovarian cancer and the like. The invention provides a foundation for the clinical combined application of the oleanolic acid and the PARP inhibitor, provides a new way and means for effectively treating the ovarian cancer, and has important clinical application value.
Description
Technical Field
The disclosure belongs to the field of medicine, and relates to application of oleanolic acid and a PARP inhibitor in preparation of a medicine for treating ovarian cancer.
Background
Malignant tumors seriously threaten human health, and are difficult to detect at the initial stage of ovarian cancer so that the ovarian cancer is usually in the middle and late stages. The treatment method of ovarian cancer patients comprises surgical treatment, radiotherapy, chemotherapy and the like. However, most ovarian cancer patients diagnosed at middle and late stages have poor surgical treatment effect, and chemotherapy becomes an important means for improving the life quality of the patients. However, the conventional chemotherapy drugs are easy to generate drug resistance and side effects, so that the enhancement of the anticancer activity of the traditional chemotherapy drugs and the reduction of the adverse reaction have important clinical significance.
In recent years, "precise therapy" based on gene detection has become an important means for treating diseases with the development of gene diagnostic techniques. Ovarian cancer has a remarkable family genetic tendency, and researches show that the genetic tendency is mainly caused by gene mutation, mainly the gene mutation of breast cancer susceptibility genes BRCA1 and BRCA 2. The incidence of ovarian cancer in normal persons is low (< 1.5%), but the incidence risk of BRCA1/2 gene mutation is obviously increased. Poly ADP Ribose Polymerase (PARP) inhibitors can target BRCA-deficient tumor cells, making development of PARP inhibitors a hotspot. Poly ADP Ribose Polymerase (PARP) is a DNA repair enzyme, PARP has multiple subunits, and PARP-1 and PARP-2, which are most studied, play an important role in the DNA damage repair process. PARP inhibitors exacerbate cellular DNA damage by blocking PARP involvement in DNA damage repair, ultimately leading to cell death. With the sequential marketing of PARP inhibitors, hope is brought to breast cancer and ovarian cancer patients, but the PARP inhibitors on the market at present have certain defects. Olaparib (Olaparib) is the first approved PARP inhibitor for the treatment of advanced ovarian cancer. Despite the advances made in the treatment of ovarian cancer by olaparib, it has a severe indication that BRCA deficient patients are highly efficacious and are less likely to benefit than those without BRCA mutations. On the other hand, the resistance of PARP inhibitors also limits their use. In recent years, more and more researches have been carried out to combine PARP inhibitors with other chemotherapeutic drugs to increase the application range, but better curative effect has not been obtained yet. Therefore, it is important and urgent to find more effective therapeutic drugs for ovarian cancer.
The combined treatment of tumors by Chinese and western medicines is one of the current research hotspots, and the combined use of the Chinese patent medicine and the western medicine with the same or similar pharmacological effects can possibly play a role in synergy, reduce the dosage of the western medicine and shorten the treatment period.
Oleanolic Acid (OA) is a pentacyclic triterpene compound occurring in nature, which is widely found in plant-derived foods and herbs. OA has certain biological activity, such as anti-inflammatory, antihyperglycemic, antihyperlipidemic, antioxidant and hepatoprotective effects.
At present, no research on the combination of oleanolic acid and olaparib for treating ovarian cancer exists, the invention aims to combine the oleanolic acid and the PARP inhibitor to achieve the synergistic treatment effect, and the invention has important clinical significance and application value.
Disclosure of Invention
In order to solve the above problems, the present invention provides a pharmaceutical composition having an anti-tumor effect, which comprises oleanolic acid and a PARP inhibitor.
In certain embodiments, the PARP inhibitors described in the present disclosure are Olaparib (Olaparib), nilapaprid (niaparib), talazolarib (Talzenna/talazolparib), fluzopprib (fluzopanib), pamiparib (pamiaparib), and PJ34.
Preferably, the PARP inhibitor is olaparide.
Furthermore, the pharmaceutical composition also comprises pharmaceutic adjuvants.
The pharmaceutical excipients are selected from one or more of diluents, flavoring agents, lubricants, glidants, and optionally disintegrants and binders.
Furthermore, the weight ratio of the oleanolic acid to the PARP inhibitor is (8). Preferably, the weight ratio of the oleanolic acid to the PARP inhibitor is 4; more preferably, the weight ratio of oleanolic acid to PARP inhibitor is 2.
The weight ratio of oleanolic acid to olaparide is 8-1, preferably, the weight ratio of oleanolic acid to olaparide is 4; more preferably, the weight ratio of oleanolic acid to olaparide is 2.
The invention aims to provide application of the pharmaceutical composition in preparing a medicine for treating tumors.
Preferably, the tumor is ovarian cancer.
The pharmaceutical composition with the anti-tumor effect combines the oleanolic acid and the PARP inhibitor to achieve the effect of synergy. Finally, the treatment effect of the combined medicine is obviously better than that of any one of the medicines of the oleanolic acid or the PARP inhibitor, and the combined medicine has clinical popularization value.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
Example 1: oleanolic acid and olaparide combined administration proliferation inhibition test in ovarian cancer cells
1. Experimental methods
2. Cell culture: digesting and centrifuging SK-OV-3 and OVACR-3 cells of ovarian cancer in logarithmic growth phase with 0.25% of trypsin, inoculating the cells into 96-well plate with 5000 cells per well after resuspension, placing the 96-well plate at 37 ℃, and containing 5% of CO 2 The cell culture chamber of (2) was cultured overnight. The following day, the divided doses were administered for 48 hours.
3. Calculation of single and combined dosing indexes:
(1) Detecting the inhibition rate of each group by adopting a tetramethyl azozolium (MTT) method and calculating the half inhibition rate IC 50 The value is obtained.
(2)IC 50 Values were calculated using Graphpad prism software.
(3) The Combination index CI (Combination index) of the oleanolic acid and the olaparide combined drug is quantified by taking the concentration of the intermediate-acting drug, namely the drug concentration when the inhibition rate is 50%, as an evaluation index, and whether the Combination of the oleanolic acid and the olaparide is synergistic, additive or antagonistic is evaluated. The specific method comprises the following steps:
CI = D1/Dx1+ D2/Dx2+ alpha (D1D 2)/(Dx 1 xDx 2) is obtained by derivation according to Chou-Talalay combined exponential method. D1 and D2 are the concentrations required by the two medicines when the two medicines are used together to generate X% inhibition effect, and DX1 and DX2 are the concentrations required by the two medicines when the two medicines are used independently to generate X% inhibition effect. A represents a parameter of the combination effect, and α =0 when the drug effect is mutual exclusion (i.e. similar combination effect). Due to the different mechanisms of action of oleanolic acid and olapari, α =0 was taken in this study. When CI >1, both antagonisms were observed, when CI =1, both antagonisms were observed as an additive, and when CI <1, both antagonisms were observed as a synergistic effect.
According to the Principle of evaluating the effect by the media-effect Principle, namely the CI index is less than 0.1, the effect has strong synergistic effect (Very string synergy); a Strong synergistic effect (Strong synergy) when the CI index is 0.1-0.3; CI index of 0.3-0.7 has synergistic effect (synergy); CI index of 0.7-0.85 has Moderate synergistic effect (Moderate synergy); the CI index is in the range of 0.85-0.90, and has weak synergistic effect (Slight synergy); the CI index is in the range of 0.90-1.10, and has a near additive effect (near additive); CI indices >1.10 and above have antagonistic effects.
4. Results of the experiment
(1) Oleanolic acid and olaparide have inhibitory effect on SK-OV-3 and OVCAR-3 cells, IC 50 The results are shown in Table 1.
TABLE 1 Oleanolic acid and Olapari in combination with a single drug/combination 48 h IC 50 (μg/mL)。
(2) The synergistic index of the two combined medicines shows that the oleanolic acid and the olapari have synergistic effect when being combined; especially, when the weight ratio of the two is 4-1.
TABLE 2 CI comparison of combination index for 48 hours for different combinations of oleanolic acid and olapari
Example 2 in vivo animal experiments of Oleanolic acid in combination with Olapari for the treatment of ovarian cancer in mice
1. Preparing the medicine: oleanolic acid and olapari are prepared by using a 2% tween 80+5% PEG 400 solution.
2. Experimental animals: BALB/c nude mice, 6-8 weeks old, female.
3. The experimental steps are as follows: taking SK-OV-3 cells in logarithmic growth phase, and 0.25% trypsinResuspending the cells in serum-free DMEM high-sugar medium after centrifugation to adjust the cell concentration to 1 × 10 7 The volume is/mL. The cell suspension was inoculated in the right anterior axilla (200. Mu.L/mouse) of nude mice. Administration was started the next day after vaccination by gavage 1 time a day for a total of 21 days. After the administration, the mice were euthanized, weighed and the subcutaneous tumor mass was removed, and the tumor weight was weighed and the tumor inhibition rate was calculated.
Calculating the tumor inhibition rate: tumor inhibition (%) = (1- (tumor weight of treatment group/tumor weight of control group)) × 100.
Weight: mouse body weights were recorded every 3 days and mouse body weight changes (W) were calculated 21 -W 0 )，W 21 Represents pre-mortem body weight, W 0 Representing the body weight before the first dose.
The two medicines are combined, Q = E (a + b)/(Ea + Eb-Ea x Eb), wherein E (a + b) is the inhibition rate of the two medicines when used together, namely the combination effect is measured, ea and Eb are the inhibition rates of the two medicines when used alone, the denominator (Ea + Eb-Ea x Eb) is the expected combination effect, and Q is the ratio of the two. When the Q value is between 0.85 and 1.15, the combination effect of the two medicines is additive (+), the Q value is synergistic (++) when the Q value is between 1.15 and 20, the Q value is more than 20 and is obvious synergistic (+++), the Q value is antagonistic when the Q value is between 0.05 and 0.85, and the Q value is less than 0.05 and is obvious antagonism.
4. Results of the experiment
The results show that the Q value of the tumor inhibition rate of the SK-OV-3 ovarian cancer mouse transplanted tumor is 1.46-1.66, and the Q value of the tumor inhibition rate is 1.15-20 when 100mg/kg of oleanolic acid and 25mg/kg, 50mg/kg and 100mg/kg of olaparide are jointly used. Especially, when the weight ratio of oleanolic acid to olaparide is 2.
TABLE 3 Effect of combination on the tumor suppression Rate of ovarian carcinoma SK-OV-3 mice transplanted tumors
P < 0.05, p < 0.01 compared to blank.
Example 3 evaluation of the safety of combination drug administration
Example 2 after mice were sacrificed, blood was collected from the orbit and centrifuged to remove serum, and the activity of glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase were measured separately to evaluate the safety of the combination. The activity of glutamic oxaloacetic transaminase and glutamic pyruvic transaminase is shown in Table 4, and the results show that the oleanolic acid and olaparide are used alone or in combination without causing the activity of glutamic oxaloacetic transaminase or glutamic pyruvic transaminase to be increased.
TABLE 4 Effect of combination on serum glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase activities of mice
In conclusion of experimental results, the combined use of oleanolic acid and olaparide in the invention is a medicine for treating ovarian cancer, wherein the molar ratio of oleanolic acid to olaparide in the combined use is (4-1), and preferably (2). Compared with the treatment effect of a single medicine, the oleanolic acid and the olaparide are prepared into a combined medicine, so that the synergistic effect is achieved, the curative effect is better, and the toxic and side effects are small.
Claims (10)
1. A pharmaceutical combination for the treatment of tumors, said combination consisting of oleanolic acid and a PARP inhibitor.
2. The pharmaceutical combination according to claim 1, wherein the PARP inhibitor is Olaparib (Olaparib), nilapartib (Niraparib), talapartib (Talzenna/Talazoparib), fluzoparib (Fluzoparib), pamiparib (pamiaparib) or PJ34.
3. The pharmaceutical composition of claim 1, further comprising a pharmaceutical excipient selected from one or more of diluents, flavoring agents, lubricants, glidants, and optionally disintegrants and binders.
4. The anti-tumor pharmaceutical composition of claim 2, wherein said PARP inhibitor is selected from olapari.
5. The antitumor pharmaceutical composition as claimed in claim 1, wherein the tumor is selected from one or more of breast cancer, ovarian cancer, cervical cancer, lung cancer, intestinal cancer, gastric cancer, esophageal cancer, liver cancer leukemia, malignant lymphoma, nasopharyngeal cancer, and pancreatic cancer.
6. The use of an anti-neoplastic pharmaceutical composition according to claim 5, wherein the neoplasm is selected from the group consisting of ovarian cancer.
7. The pharmaceutical composition according to claim 1, wherein the weight ratio of oleanolic acid to PARP inhibitor is 8; more preferably, the weight ratio of oleanolic acid to PARP inhibitor is 2.
8. The pharmaceutical composition according to claim 2, wherein the weight ratio of oleanolic acid to olaparide is 8 to 1, preferably the weight ratio of oleanolic acid to olaparide is 4 to 1; more preferably, the weight ratio of oleanolic acid to olaparide is 2.
9. Use of a pharmaceutical composition according to any one of claims 1 to 8 for the preparation of a medicament for the treatment of tumors.
10. Use according to claim 9, wherein the pharmaceutical composition is for the manufacture of a medicament for the treatment of tumor cell proliferation.
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| CN202211142307.6A CN115364228A (en) | 2022-09-20 | 2022-09-20 | Pharmaceutical composition for treating ovarian cancer |
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| CN202211142307.6A CN115364228A (en) | 2022-09-20 | 2022-09-20 | Pharmaceutical composition for treating ovarian cancer |
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Application publication date: 20221122 |