CN113599370B - Application of 8-OH-DPAT and derivatives thereof in preparation of antitumor drugs - Google Patents
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- ASXGJMSKWNBENU-UHFFFAOYSA-N 8-OH-DPAT Chemical compound C1=CC(O)=C2CC(N(CCC)CCC)CCC2=C1 ASXGJMSKWNBENU-UHFFFAOYSA-N 0.000 title claims abstract description 55
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 19
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title description 2
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 19
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 19
- 206010033128 Ovarian cancer Diseases 0.000 claims abstract description 13
- 206010061535 Ovarian neoplasm Diseases 0.000 claims abstract description 13
- 201000007270 liver cancer Diseases 0.000 claims abstract description 13
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 5
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims abstract description 4
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 4
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 4
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- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
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- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- 102100027499 5-hydroxytryptamine receptor 1B Human genes 0.000 description 1
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- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
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- 150000002148 esters Chemical class 0.000 description 1
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- 239000003112 inhibitor Substances 0.000 description 1
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- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Emergency Medicine (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides application of 8-OH-DPAT or a derivative thereof and a pharmaceutical composition containing the 8-OH-DPAT or the derivative thereof in preparing anti-tumor drugs. The 8-OH-DPAT has obvious and wide antitumor activity, has an inhibiting effect on the growth of various human tumor cells cultured in vitro, such as breast cancer, colorectal cancer, ovarian cancer, lung cancer, liver cancer and the like, and can obviously inhibit the tumorigenicity of breast cancer MDA-MB-231LM2 cells in a nude mouse, so that the 8-OH-DPAT and the derivatives thereof can be used as antitumor drugs.
Description
Technical Field
The invention relates to the technical field of biomedical application, in particular to anti-tumor activity of 8-OH-DPAT and derivatives thereof and application thereof in preparing anti-tumor drugs.
Background
8-OH-DPAT has a chemical name of 8-hydroxy-2- (di-propylamino) tetrahydronaphthalene 8-OH-DPAT (English name: 8-hydroxy-2- (di-N-propylamine) tetralin), and is a pale yellow powder with a chemical formula of C 16 H 25 NO, molecular weight 247.37600, readily soluble in methanol (about 49 mg/mL) and DMSO (about 49 mg/mL), insoluble in water. 8-OH-DPAT is a classical 5-HT1A agonist, pIC 50 8.19. Has nearly 1000-fold selectivity for the 5-HT1 binding site subtype,its half-life was 1.5 hours. 8-OH-DPAT has only a weak effect on 5-HT1B, pIC 50 5.42±0.08 (n=5). At concentrations below 100nM, 8-OH-DPAT had no effect on 5-HT 1B. Previous studies have found that 8-OH-DPAT is capable of reducing lipofuscin from autophagy sources and from photoreceptor extracellular segments, increasing antioxidant protective capacity, and reducing oxidative damage in human RPE cells. Intravenous injection of 8-OH-DPAT in patients with hypotension can rapidly reverse bradycardia response in severe bleeding. 8-OH-DPAT is a lipophilic molecule, can penetrate the blood brain barrier, and can play a central role as an antiemetic.
Disclosure of Invention
The invention adopts the following technical scheme:
the invention provides application of 8-OH-DPAT or a derivative thereof in preparing a medicine for preventing and/or treating tumors;
the invention also provides application of the pharmaceutical composition containing 8-OH-DPAT in preparing antitumor drugs;
further, the pharmaceutical compositions of 8-OH-DPAT or derivatives thereof include, but are not limited to, tablets, capsules, oral solutions, pills, granules, powders, aerosols, patches, ointments, paints, suppositories, and/or injections;
further, the 8-OH-DPAT is shown as a formula (I):
further, the derivatives of 8-OH-DPAT include, but are not limited to, pharmaceutically acceptable salts thereof, ethers thereof, esters thereof, prodrugs thereof, metabolites thereof, solvates thereof, or crystals thereof;
further optionally, the pharmaceutical composition further comprises a conventional antineoplastic agent; further preferred, the conventional anti-tumor agents include, but are not limited to, chemotherapeutic agents, bio-targeted therapeutic agents, metabolic therapeutic agents, or immunotherapeutic agents; or still further, the chemotherapeutic agents include, but are not limited to, doxorubicin, paclitaxel, or platins; or still further, the bio-targeted therapeutic includes, but is not limited to, monoclonal antibodies or small molecule inhibitors; or still further, the metabolic class therapeutic agent comprises metformin or a statin; or further, the immune therapeutic drug comprises a drug targeting PD-1, PD-L1 or CTLA-4 and the like;
further, the antitumor drug is used for surgical excision, chemotherapy or radiotherapy;
further, the effects of the antitumor agents include, but are not limited to, inhibition of tumor growth and/or metastasis;
further, the anti-tumor drugs have the effects of inhibiting breast cancer, intestinal cancer, ovarian cancer, lung cancer and liver cancer cells; still further, the bowel cancer includes, but is not limited to, colon cancer;
still further, the inhibition of breast cancer includes, but is not limited to, inhibition of breast cancer cells MDA-MB-231 or MDA-MB-231LM 2;
still further, inhibition of ovarian cancer includes, but is not limited to, inhibition of ovarian cancer cell a 2870;
still further, the inhibition of lung cancer includes, but is not limited to, inhibition of lung cancer cell a549 or lung cancer cell HCT 1299;
further, inhibition of intestinal cancer includes, but is not limited to, inhibition of intestinal cancer cell HCT 116;
further, the inhibition of liver cancer includes, but is not limited to, inhibition of liver cancer cell MHCC-97L.
Drawings
FIG. 1 shows the growth inhibition curves of 8-OH-DPAT at different concentrations on breast cancer cells MDA-MB-231LM224h and 48 h;
FIG. 2 shows growth inhibition curves of 8-OH-DPAT at different concentrations for breast cancer cells MDA-MB-231 24h and 48 h;
FIG. 3 shows growth inhibition curves of 8-OH-DPAT at various concentrations for ovarian cancer cells A2870 24h and 48 h;
FIG. 4 shows growth inhibition curves of 8-OH-DPAT at various concentrations for lung cancer cells A549 for 24h and 48 h;
FIG. 5 shows growth inhibition curves of different concentrations of 8-OH-DPAT on lung cancer cells HCT1299 24h and 48 h;
FIG. 6 shows growth inhibition curves of different concentrations of 8-OH-DPAT versus intestinal cancer cells HCT116 h and 48 h;
FIG. 7 shows growth inhibition curves of different concentrations of 8-OH-DPAT on liver cancer cells MHCC-97L 24h and 48 h;
FIG. 8 shows tumor volume curves at different time points of 8-OH-DPAT concentration versus MDA-MB-231LM2 cell growth in nude mice;
FIG. 9 shows tumor weight statistics of different concentrations of 8-OH-DPAT versus end point of MDA-MB-231LM2 cell growth in nude mice;
FIG. 10 shows the effect of different concentrations of 8-OH-DPAT on nude mice body weight.
Advantageous effects
1.8-OH-DPAT has obvious and wide antitumor activity, and can inhibit the growth of various in vitro cultured human tumor cells such as breast cancer, colorectal cancer, ovarian cancer, lung cancer, liver cancer, etc., wherein 48h IC 50 119.4.+ -. 4.97. Mu.M (breast cancer cell MDA-MB-231LM 2), 468.03.+ -. 19.37. Mu.M (breast cancer cell MDA-MB-231), 29.00.+ -. 20.46. Mu.M (ovarian cancer cell A2870), 494.36.+ -. 142.16. Mu.M (lung cancer cell A549), 583.+ -. 146.90. Mu.M (lung cancer cell HCT 1299), 88.23.+ -. 3.90. Mu.M (intestinal cancer cell HCT 116), 333.77.+ -. 38.73. Mu.M (liver cancer cell MHCC-97L), respectively.
2.8-OH-DPAT can obviously inhibit the tumor formation capability of breast cancer cells MDA-MB-231LM2 cells in a nude mouse body, the inhibition rate can reach 74.87 +/-14.08 percent, the tumor volume and the weight are obviously different, and the method has statistical significance (p < 0.01).
Detailed Description
Example 1: CCK8 colorimetric method for investigating cytotoxicity of 8-OH-DPAT
The effect of 8-OH-DPAT on the cytotoxicity 8-OH-DPAT of human colorectal cancer HCT116 cells, SW480 cells, ovarian cancer A2780 cells, lung cancer H1299 cells, breast cancer MDA-MB-231 and MDA-MB-231LM2 cells and liver cancer cells MHCC-97L cells on growth inhibition is compared by adopting a CCK8 colorimetric method. The cells were seeded at 8000 cells/well in 96-well plates, and after 24 hours of seeding, the drugs were diluted to 0, 0.01, 0.1, 1, 10, 20, 40, 80, 160, 320, 640. Mu.M, and the medium in the original wells was discarded, and 100. Mu.l of each well was added to the corresponding well, and 4 replicate wells were used. After adding 10 μl of CCK8 to each well for 3 hours at 24 hours and 48 hours of treatment, respectively, the OD value at a450 was detected by a multifunctional microplate reader and the inhibition ratio was calculated.
The results are shown in FIGS. 1-7, which suggest that cell proliferation can be significantly inhibited. FIG. 1 shows growth inhibition curves for MDA-MB-231LM224h and 48h of breast cancer cells treated with different concentrations of 8-OH-DPAT, wherein 48h of IC 50 119.4+ -4.97 μM; FIG. 2 shows growth inhibition curves for MDA-MB-231 24h and 48h of breast cancer cells treated with different concentrations of 8-OH-DPAT, wherein 48h of IC 50 468.03 + -19.37 μm; FIG. 3 shows growth inhibition curves for ovarian cancer cells A2870 24h and 48h treated with 8-OH-DPAT at various concentrations, wherein 48h of IC 50 29.00.+ -. 20.46. Mu.M; FIG. 4 shows growth inhibition curves for lung cancer cells A54924h and 48h treated with 8-OH-DPAT at various concentrations, where 48h of IC 50 494.36.+ -. 142.16. Mu.M; FIG. 5 shows growth inhibition curves for lung cancer cells HCT1299 24h and 48h treated with 8-OH-DPAT at different concentrations, wherein 48h of IC 50 583+ -146.90 μm; FIG. 6 shows growth inhibition curves of intestinal cancer cells HCT116 for 24h and 48h treated with different concentrations of 8-OH-DPAT, wherein 48h of IC 50 88.23 + -3.90 μm; FIG. 7 shows growth inhibition curves of liver cancer cells MHCC-97L 24h and 48h treated with 8-OH-DPAT at different concentrations, wherein 48h IC 50 333.77.+ -. 38.73. Mu.M.
Example 2: influence of 8-OH-DPAT on tumor growth of nude mice with in-situ engrafted tumor of human breast cancer cells MDA-MB-231LM2
Adapting 6-8 week old BALB/C female nude mice to environment for about 1 week, digesting MDA-MB-231LM2 cells with pancreatin, centrifuging at 1000rpm for 5min, adding 5mL fresh FBS-free DMEM, washing, counting, and adjusting concentration to 2×10 7 Each cell/mL was inoculated to the fat pad of the mice at 100. Mu.l each. The tumor size is 1-20 mm 3 Administration was then started.
Randomly divide into 2 groups of 108-OH-DPAT (5 mg/kg) dosing groups, solvent blank, respectively. Nude mice were numbered and given by intraperitoneal injection of 8-OH-DPAT in groups following tumor inoculation, 1 time daily, 100. Mu.L of drug (1 mg/ml in 5% DMSO+30% PEG300+10% Tween-80+55% sterile water) or solvent blank (5% DMSO+30% PEG300+10% Tween 80+55% sterile water) per mouse for 3 weeks. Mice were fasted on the last day of dosing without water and dissected the next day. The body weight and tumor volume of the nude mice were recorded every three days during the experiment, and the growth of the nude mice was observed. End point of experiment with CO 2 Nude mice were sacrificed by asphyxiation, tumor tissues were taken, tumor weights were measured and inhibition ratios were calculated, inhibition ratio= (control tumor weight-dosing tumor weight/control tumor weight) ×100%. The results are shown in FIGS. 8 and 9,8-OH-DPAT group can significantly inhibit the growth of tumor in nude mice vaccinated with MDA-MB-231LM2, but does not affect the body weight of the mice: FIG. 8 shows the effect of different concentrations of 8-OH-DPAT on MDA-MB-231LM2 tumor volume in nude mice, and shows that the effect can significantly inhibit tumor growth; FIG. 9 shows the effect of different concentrations of 8-OH-DPAT on the weight of MDA-MB-231LM2 tumor in nude mice, and shows that the effect can significantly inhibit the growth of tumor; FIG. 10 shows the effect of different concentrations of 8-OH-DPAT on the weight of nude mice, showing that the effect on the weight of mice is not affected, and that 8-OH-DPAT has no obvious toxic or side effect.
While the invention has been described with reference to the preferred embodiments, it is not intended to limit the invention thereto, but rather to limit the invention to those skilled in the art, without departing from the spirit and scope of the invention.
Claims (10)
- The application of 8-OH-DPAT in preparing anti-tumor drugs for preventing and/or treating tumor is characterized in that the 8-OH-DPAT is shown as a formula (I):the antitumor drug has the effect of inhibiting breast cancer, intestinal cancer, ovarian cancer and/or liver cancer cells.
- 2. The use according to claim 1, wherein the bowel cancer is colorectal or rectal cancer.
- 3. Use of a pharmaceutical composition comprising 8-OH-DPAT for the manufacture of a medicament for the prevention and/or treatment of an anti-tumor, wherein the 8-OH-DPAT is represented by formula (I):the antitumor drug has the effect of inhibiting breast cancer, intestinal cancer, ovarian cancer and/or liver cancer cells.
- 4. The use according to claim 3, wherein the pharmaceutical composition of 8-OH-DPAT is a tablet, capsule, oral solution, pill, granule, powder, aerosol, patch, ointment, varnish, suppository or injection.
- 5. The use according to claim 3 or 4, wherein the pharmaceutical composition further comprises a conventional anti-tumor drug, which is a chemotherapeutic drug, a bio-targeted therapeutic drug, a metabolic therapeutic drug or an immunotherapeutic drug.
- 6. The use according to claim 5, wherein the anti-tumor drug acts to inhibit tumor growth and/or metastasis.
- 7. The use according to claim 1 or 3, wherein the inhibition of breast cancer is an inhibition of breast cancer cells MDA-MB-231 or MDA-MB-231LM 2.
- 8. The use according to claim 1 or 3, wherein the inhibition of ovarian cancer is an inhibition of ovarian cancer cell a 2870.
- 9. The use according to claim 1 or 3, wherein the inhibition of intestinal cancer is inhibition of intestinal cancer cell HCT 116.
- 10. The use according to claim 1 or 3, wherein the inhibition of liver cancer is an inhibition of liver cancer cell mhc c-97L.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992004014A2 (en) * | 1990-09-04 | 1992-03-19 | Miles Inc. | REGULATION OF NEOPLASTIC CELL PROLIFERATION VIA A NOVEL 5HT1a RECEPTOR |
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