CN109223742A - The purposes of joint Simvastatin and melbine - Google Patents
The purposes of joint Simvastatin and melbine Download PDFInfo
- Publication number
- CN109223742A CN109223742A CN201811170714.1A CN201811170714A CN109223742A CN 109223742 A CN109223742 A CN 109223742A CN 201811170714 A CN201811170714 A CN 201811170714A CN 109223742 A CN109223742 A CN 109223742A
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- simvastatin
- melbine
- joint
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- mouse
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- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 title claims abstract description 67
- 229960002855 simvastatin Drugs 0.000 title claims abstract description 67
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 title claims abstract description 67
- 239000003814 drug Substances 0.000 claims abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 11
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 10
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 7
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 6
- 201000007270 liver cancer Diseases 0.000 claims abstract description 6
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 6
- 201000005202 lung cancer Diseases 0.000 claims abstract description 5
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 14
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 6
- 229940123208 Biguanide Drugs 0.000 claims 3
- 150000004283 biguanides Chemical class 0.000 claims 3
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 abstract description 2
- 229960003105 metformin Drugs 0.000 abstract description 2
- 208000019065 cervical carcinoma Diseases 0.000 abstract 1
- 230000002195 synergetic effect Effects 0.000 abstract 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 12
- 229940079593 drug Drugs 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 210000000577 adipose tissue Anatomy 0.000 description 4
- 238000011065 in-situ storage Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 210000005075 mammary gland Anatomy 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 238000011081 inoculation Methods 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 101000600434 Homo sapiens Putative uncharacterized protein encoded by MIR7-3HG Proteins 0.000 description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 description 2
- 206010027458 Metastases to lung Diseases 0.000 description 2
- 102100037401 Putative uncharacterized protein encoded by MIR7-3HG Human genes 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000004043 dyeing Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 102220002645 rs104894309 Human genes 0.000 description 2
- CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 206010018473 Glycosuria Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 239000006481 glucose medium Substances 0.000 description 1
- 244000144993 groups of animals Species 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 208000026037 malignant tumor of neck Diseases 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 231100001160 nonlethal Toxicity 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Classifications
-
- 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
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The present invention relates to Simvastatins (Simvastatin) and melbine (Metformin), in particular to combine the purposes of Simvastatin and melbine.Belong to Western medicine field.The present invention combines the purposes of Simvastatin and melbine, it is characterized in that: the joint Simvastatin and melbine application in preparation of anti-tumor drugs.Simvastatin and melbine are simultaneously used in liver cancer, breast cancer, lung cancer, there is significant antitumor action in cervical carcinoma, and the two synergistic antitumor effect is relatively used alone more preferably.
Description
Technical field
The present invention relates to Simvastatins (Simvastatin) and melbine (Metformin), in particular to combine pungent cut down
The purposes of statin and melbine.Belong to Western medicine field.
Background technique
Simvastatin is developed by United States Merck company, be using Lovastatin as raw material it is semi-synthetic made of HMG-CoA restore
Enzyme inhibitor, the product obtain U.S. FDA approval in December, 1991 in Initial Public Offering in 1988, are treatment primary hypercholesteremias
The drug of disease.Simvastatin is liposoluble substance.Can the effectively development of prevention of arterial atherosis and heart disease recurrence, reduce non-
Lethal myocardial infarction and myocardial vascular re-form the danger of art.Melbine pungent cuts down him for treating diabetes choice drug
Spit of fland and melbine have not been reported in terms for the treatment of tumour.
The Pathological experiment discovery of related mouse model is used in combination in we in the research for carrying out tumor pathogenesis, will be pungent
It cuts down statin and melbine is used in combination has the function of stronger inhibition implanted solid tumor growth.
Summary of the invention
The object of the present invention is to provide a kind of purposes for combining Simvastatin and melbine, especially combine and pungent cut down him
Spit of fland and melbine application in preparation of anti-tumor drugs.
The technical scheme is that the purposes of joint Simvastatin and melbine, it is characterized in that: the joint is pungent
Cut down statin and melbine application in preparation of anti-tumor drugs.
In the preparation of antitumor drugs, Simvastatin dosage is 60- to the joint Simvastatin and melbine
120mg/kg/d, melbine dosage are 800-1600mg/kg/d.
Application of the joint Simvastatin and melbine in preparation anti-liver cancer and anti-tumour medicine.
Application of the joint Simvastatin and melbine in preparation anti-lung cancer tumour medicine.
The joint Simvastatin and melbine is preparing the application in breast-tumor resisting medicine.
The invention has the advantages that clinically lacking the drug for the treatment of anti-tumor drug at present, faced by scientific experiment confirmation
Bed can have the function of stronger this new purposes of inhibition tumour growth by the way that Simvastatin and melbine to be used in combination.
Joint Simvastatin and melbine provided by the invention can have the function of good anti-inhibition tumour growth, further, since
Simvastatin can clinically be carried out for the drug for the treatment of hypercholesterolemia to be used, and same melbine is also in treatment glycosuria
Disease is clinically carried out to be used, meanwhile, Simvastatin and melbine clinically use simultaneously, and there is no mutual pairs to make
With, therefore have the advantages that clinical certified toxic side effect is relatively small for relatively other antitumor chemotherapeutic agents.
Detailed description of the invention
Fig. 1 is the growth knurl figure that Simvastatin and melbine inhibition mouse tumor is used in combination；
Fig. 2 is the Lung metastases effect picture that joint Simvastatin and melbine can significantly inhibit tumour；
Fig. 3 is that joint Simvastatin and melbine can extend Overall survival curve graph；
Fig. 4 is the effect picture that joint Simvastatin and melbine can significantly inhibit tumor cell proliferation.
Specific embodiment
The present invention is confirmed by pharmacodynamic experiment below.In mouse model, the dosage of Simvastatin is
7.5-15mg/kg/d, melbine dosage are 100-200mg/kg/d.The dosage according to the model of mouse is calculated in people
Body combines Simvastatin and melbine in the preparation of antitumor drugs, and Simvastatin dosage is 60-120mg/kg/d, and diformazan is double
Guanidine dosage is 800-1600mg/kg/d.
Cell: 4T1, B16, HepG2, Huh7, Hep3B, MDA-MB-231, BT549, A549, H1299, SiHa, C33A
Drug and reagent: Simvastatin, melbine, DMEM high glucose medium, MEM culture medium, fetal calf serum, green strepto-
Plain dual anti-, crystal violet
Experimental animal: BalB/C/, C57
Experimental group and method:
In BalB/C mouse, in mammary gland of mouse fat pad in-situ inoculating 4T1 cell；It is thin in C57 mouse hypodermic inoculation B16
Born of the same parents.It after tumor volume reaches 4mm*4mm, is administered by way of stomach-filling, Simvastatin is used alone in grouping control group
(7.5-15mg/kg/d) is used alone melbine (100-200mg/kg/d), Simvastatin and melbine is used in combination
Group.After 14 days drug-treateds, knurl, lung tissue are collected；Or in administration until dead mouse, records its life cycle.
As shown in Figure 1, Fig. 1 is the growth that Simvastatin and melbine inhibition mouse tumor is used in combination: in BalB/C
It is different by way of gastric infusion (daily stomach-filling is primary) in mammary gland of mouse fat pad in-situ inoculating 4T1 cell in mouse
Concentration, the knurl figure that Simvastatin (Sva) and melbine (Met) mouse after 14 days is used alone or in combination.Wherein A, which is grouped, is
Simvastatin 7.5mg/kg/d is used alone in control group, and melbine 100mg/kg/d is used alone, Simvastatin is used in combination
7.5mg/kg/d and melbine 100mg/kg/d group；B grouping is control group, Simvastatin 7.5mg/kg/d is used alone, single
It solely uses melbine 200mg/kg/d, Simvastatin 7.5mg/kg/d and melbine 200mg/kg/d group is used in combination；C points
Group is control group, Simvastatin 15mg/kg/d is used alone, and melbine 100mg/kg/d is used alone, pungent cut down is used in combination
Statin 15mg/kg/d and melbine 100mg/kg/d group；D is that grouping is control group, Simvastatin 15mg/kg/ is used alone
D is used alone melbine 200mg/kg/d, Simvastatin 15mg/kg/d and melbine 200mg/kg/d group is used in combination.
As the result is shown: after Simvastatin is handled, the tumor size of B16 is reduced significantly and the fragmentation effect of Simvastatin has dosage
Dependence effect.That is: the growth of tumour can be significantly inhibited using joint Simvastatin and melbine, prompt joint Simvastatin and
Melbine is that one kind can be applied to anti-tumor drug, being capable of application in preparation of anti-tumor drugs.It is described pungent to cut down in human body
Statin dosage is 60-120mg/kg/d, and melbine dosage is 800-1600mg/kg/d.
As shown in Fig. 2, Fig. 2 is the Lung metastases that joint Simvastatin and melbine can significantly inhibit tumour；Wherein A be
Mouse lung in mammary gland of mouse fat pad in-situ inoculating 4T1 cell in BalB/C mouse, by way of gastric infusion, after 14 days
Tissue, grouping are as follows: Simvastatin 15mg/kg/d is used alone in control group, and melbine 100mg/kg/d, joint is used alone
Use Simvastatin 15mg/kg/d and melbine 100mg/kg/d group；B is statistical analysis each group mouse Pulmonary metastasis focuses number
It influences；C is each group mouse lung tissue HE dyeing；
As shown in figure 3, Fig. 3 is that joint Simvastatin and melbine can extend Overall survival, wherein A is small in BalB/C
In mouse, in mammary gland of mouse fat pad in-situ inoculating 4T1 cell；B is in C57 mouse hypodermic inoculation B16 cell.Above two groups of animals
In model, by way of gastric infusion, packet transaction: Simvastatin 15mg/kg/d is used alone in control group, individually makes
With melbine 100mg/kg/d, Simvastatin 15mg/kg/d and melbine 100mg/kg/d group is used in combination, records mouse
Survival number of days simultaneously draws survivorship curve.
As shown in figure 4, Fig. 4 is the proliferation that joint Simvastatin and melbine can significantly inhibit tumour cell.In liver cancer
Cell line (HepG2, Huh7, Hep3B), breast cancer cell (MDA-MB-231, BT549), lung carcinoma cell (A549, H1299), palace
In neck cancer cell (SiHa, C33A), packet transaction: control group, 1 μM of Simvastatin, 10mM melbine, 1 μM of Simvastatin with
10mM melbine was jointly processed by group, through 37 degrees Celsius of the culture medium containing said medicine, carbon dioxide culture 72 hours of 5%
Afterwards, equal number of cell inoculation is continued to culture 10-14 days, crystallized purple dyeing display in the culture medium of not drug containing.
It is slightly reduced in the clone formation number school control group that Simvastatin, melbine group cell is used alone as the result is shown, joint
The number of Simvastatin and melbine group Clone formation then substantially reduces.Show to be used in combination Simvastatin and melbine can
Significantly inhibit the proliferation of tumour cell.Prompt joint Simvastatin and melbine are that one kind can be applied to anti-liver cancer and anti-tumour, resist
It, can be in preparation anti-liver cancer and anti-tumour, anti-lung cancer tumour, breast-tumor resisting medicine in lung cancer tumor, breast-tumor resisting medicine
Using.
The common knowledge of part and the english abbreviation category industry that the present embodiment does not describe in detail, may search on the net
It arrives, does not describe one by one here.
Claims (5)
1. the purposes of joint Simvastatin and melbine, it is characterized in that: the joint Simvastatin and melbine is being made
Application in standby anti-tumor drug.
2. the purposes of joint Simvastatin and melbine according to claim 1, cuts down it is characterized in that: the joint is pungent
In the preparation of antitumor drugs, Simvastatin dosage is 60-120mg/kg/d for statin and melbine, and melbine dosage is
800-1600mg/kg/d。
3. the purposes of Simvastatin according to claim 1 or 2, it is characterized in that: the joint Simvastatin and diformazan
Application of the biguanides in preparation anti-liver cancer and anti-tumour medicine.
4. the purposes of Simvastatin according to claim 1 or 2, it is characterized in that: the joint Simvastatin and diformazan
Application of the biguanides in preparation anti-lung cancer tumour medicine.
5. the purposes of Simvastatin according to claim 1 or 2, it is characterized in that: the joint Simvastatin and diformazan
Biguanides is preparing the application in breast-tumor resisting medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811170714.1A CN109223742A (en) | 2018-10-09 | 2018-10-09 | The purposes of joint Simvastatin and melbine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811170714.1A CN109223742A (en) | 2018-10-09 | 2018-10-09 | The purposes of joint Simvastatin and melbine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109223742A true CN109223742A (en) | 2019-01-18 |
Family
ID=65054951
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811170714.1A Pending CN109223742A (en) | 2018-10-09 | 2018-10-09 | The purposes of joint Simvastatin and melbine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109223742A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114767692A (en) * | 2022-04-15 | 2022-07-22 | 中国科学院化学研究所 | Combined medicine of demethylzelaronal and metformin |
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2018
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| CN103371991A (en) * | 2012-04-18 | 2013-10-30 | 中国人民解放军第二军医大学 | Application of dimethyldiguanide in preparation of medicaments for preventing or treating hepatocellular carcinoma |
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Application publication date: 20190118 |