CN106860462A - The application of perhexiline and oxaliplatin medication in terms for the treatment of stomach cancer and colorectal cancer - Google Patents
The application of perhexiline and oxaliplatin medication in terms for the treatment of stomach cancer and colorectal cancer Download PDFInfo
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- CN106860462A CN106860462A CN201710104046.1A CN201710104046A CN106860462A CN 106860462 A CN106860462 A CN 106860462A CN 201710104046 A CN201710104046 A CN 201710104046A CN 106860462 A CN106860462 A CN 106860462A
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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
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
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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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4458—Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
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Abstract
The invention discloses the application of perhexiline and oxaliplatin medication in terms for the treatment of stomach cancer and colorectal cancer.Present invention research display, perhexiline can significantly inhibit growth, propagation and the clonality of stomach cancer and colorectal cancer cell, the apoptosis of induction stomach cancer and colorectal cancer cell, suppress invasion and attack and the transfer ability of stomach cancer and colorectal cancer cell, there is significant therapeutic effect to stomach cancer and colorectal cancer, therefore can be used for the medicine of stomach cancer and intestinal cancer.The present invention provide not only a kind of new opplication of perhexiline, the clinical practice field of perhexiline is expanded, but also there is provided perhexiline and new departure of oxaliplatin medication treatment stomach cancer and colorectal cancer, the selection of the chemotherapy regimen of stomach cancer and colorectal cancer is increased, with good potential applicability in clinical practice.
Description
Technical field
The invention belongs to pharmaceutical technology field.More particularly, to perhexiline and oxaliplatin medication in treatment
Application in terms of stomach cancer and colorectal cancer.
Background technology
Stomach cancer and intestinal cancer are gastroenteric tumors common in world wide, are ranked first in the various malignant tumours of China, are
One of Etiological of causing death in global range, and there is very big difficulty in clinical treatment.
Research shows that suitable drug combination can play the effect of Synergistic, realizes more preferable therapeutic purposes.But
It is that types of drugs is on the high side, the interaction between different pharmaceutical is also different, and cooperation is bad possibly even to influence medicine
Curative effect or toxicity increase.Therefore, the screening study of the drug combination medicine in terms for the treatment of of cancer has great importance.
Perhexiline is a kind of calcium-ion channel antagonists, is acted on stream in Ca2+ is suppressed, energy vasodilator smooth muscle,
Obvious coronary artery dilator, increases CF, and to angina pectoris effect preferably, clinic is mainly used in treating angina pectoris.Simultaneously
VA is clinically also used for, especially the patient invalid to other antiarrhymics, this product tends to prove effective.Enter
One step research finds that perhexiline can also suppress the catabolism of intracellular aliphatic acid and promote autophagy, there are some researches show piperazine
Gram former times woods can to a certain extent kill leukaemia.At present, there are no perhexiline be applied to stomach cancer and intestinal cancer etc. its
The report of his disease areas.
In addition, oxaliplatin is an eka-platinium kind anti-cancer drugs, phase associated with perhexiline and oxaliplatin is also there are no at present
Close research and report.
The content of the invention
The technical problem to be solved in the present invention is to overcome the shortcomings of existing stomach cancer and intestinal cancer medicine and perhexiline
The limitation of application, there is provided a kind of new anti-gastric cancer and intestinal cancer therapeutic regimen.
It is an object of the invention to provide the medicine that perhexiline and oxaliplatin combination prevent and treat stomach cancer and/or intestinal cancer in preparation
The application of aspect.
Another object of the present invention is to provide a kind for the treatment of stomach cancer for including perhexiline and oxaliplatin and/or intestinal cancer
Medicine.
Above-mentioned purpose of the present invention is achieved through the following technical solutions：
Present invention research display, perhexiline has good prevention effect to stomach cancer and colorectal cancer, therefore can be applied to stomach
The preventing and treating of cancer and colorectal cancer.And further research display, perhexiline and oxaliplatin combination can realize to stomach cancer and/
Or the Synergistic therapeutic action of intestinal cancer, significantly improve the therapeutic effect to stomach cancer and/or intestinal cancer.
Therefore, perhexiline and oxaliplatin combination is preparing preventing and treating（Including preventing and/or treating）Stomach cancer and/or intestinal cancer
Medicine in terms of application, all within protection scope of the present invention.
Wherein it is preferred to, the intestinal cancer is colorectal cancer.
Preferably, the stomach cancer is the phase stomach cancers of Ι to IV.
It is highly preferred that the stomach cancer is IV phase stomach cancer.
It is highly preferred that the colorectal cancer is the phase colorectal cancers of Ι to IV.
It is highly preferred that the colorectal cancer is IV phase colorectal cancer.
In addition, the medicine of the treatment stomach cancer and/or intestinal cancer refer to suppress stomach cancer cell and/or colon-cancer cell growth,
Propagation and/or clonality, suppress the invasion and attack and/or transfer of stomach cancer cell and/or colon-cancer cell, and/or induction stomach cancer
The medicine of the apoptosis of cell and/or colon-cancer cell.
Preferably, the stomach cancer cell is gastric carcinoma cells HGC27 or MGC803；The colon-cancer cell is that human colon carcinoma is thin
Born of the same parents HCT 116 or human colon adenocarcinoma cell DLD-1.
A kind of medicine for preventing and treating stomach cancer and/or intestinal cancer for including perhexiline or its salt and oxaliplatin, also at this
Within the protection domain of invention.
Further, the medicine can also be including its pharmaceutically acceptable carrier etc..
The invention has the advantages that：
Therapeutic action present invention firstly discloses perhexiline and its salt to stomach cancer and colorectal cancer, can significantly inhibit stomach cancer
The apoptosis of growth and propagation with colorectal cancer cell, induction stomach cancer and colorectal cancer cell, and suppress its transfer, to knot stomach cancer
There is significant curative effect with the carcinoma of the rectum, the preventing and treating aspect of stomach cancer and colorectal cancer is can be applied to.Meanwhile, research first demonstrates piperazine
Gram former times woods and oxaliplatin medication have more significant therapeutic effect to stomach cancer and colorectal cancer, realize Synergistic
Effect.
The invention provides perhexiline and oxaliplatin medication treatment stomach cancer and colorectal cancer new departure, not only
For the treatment of stomach cancer and colorectal cancer provides a kind of new medicine and therapy approach, also for the application of perhexiline is provided
New field.
Brief description of the drawings
Fig. 1 is that perhexiline processes survivaling cell ratio after stomach cancer and colorectal cancer cell.
Fig. 2 be perhexiline to stomach cancer and colorectal cancer cell into knurl influence.
Fig. 3 is perhexiline to stomach cancer and colorectal cancer cell proliferative effect.
Fig. 4 is the influence that perhexiline is shifted to stomach cancer and colorectal cancer cell.
Fig. 5 is the influence that perhexiline is attacked to stomach cancer and colorectal cancer cell.
Fig. 6 is that perhexiline is alone or joint oxaliplatin processes survivaling cell ratio after stomach cancer and colorectal cancer cell.
Specific embodiment
The present invention, but embodiment are further illustrated below in conjunction with Figure of description and specific embodiment not to the present invention
Limit in any form.Unless stated otherwise, reagent, the method and apparatus that the present invention is used are for the art is routinely tried
Agent, method and apparatus.
Unless stated otherwise, following examples agents useful for same and material are purchased in market.
The perhexiline of embodiment 1 is to stomach cancer and colorectal cancer cell and its influence into knurl
1st, experiment material
（1）Medicine：Perhexiline clinically commonly uses its maleate, and the present embodiment is with perhexiline maleate as experimental drug
Thing.
The chemical structural formula of perhexiline maleate is as follows：
（2）Cancer cell：
Stomach cancer cell：Gastric carcinoma cells HGC27 and MGC803；
Colorectal cancer cell：Human colon cancer cell HCT 116 and human colon adenocarcinoma cell DLD-1.
（3）Apoptosis kit purchased in market.
2nd, experiment packet
（1）Control group：Blank, i.e. cancer cell are without any drug-treated.
（2）Experimental group：Cancer cell is processed using perhexiline maleate.
3rd, influence of the Flow cytometry perhexiline maleate to stomach cancer and colorectal cancer cell apoptosis
（1）We complete colorectal cancer cell in 12 orifice plates, after its is adherent, add 0 μM（Compare）、3μM、4μM（Or
5μM）Perhexiline maleate treatment cell 24h, then by Apoptosis by Flow Cytometry situation.
Specific method is as follows：
1）After HGC27 the and MGC803 cells of exponential phase, HCT 116 and DLD-1 cells are digested with pancreatin, 1 ~ 2 is taken ×
105Cell is uniformly taped against in 12 orifice plates.
2）After the culture medium containing various concentrations perhexiline maleate after cell attachment, is replaced with, 24h is incubated.
3）After vitellophag, the method treatment cell according to apoptosis detection kit, Annexin V and PI dyeing is completed
Pass through flow cytomery Apoptosis situation afterwards.
（2）Experimental result
Result is as shown in figure 1, the percentage shown in Fig. 1 is double-negative for Annexin V and PI（That is survivaling cell）Ratio, uses
After perhexiline maleate treatment, the death toll of stomach cancer and colorectal cancer cell substantially increases, and shows that perhexiline can be induced
Stomach cancer and colorectal cancer cell apoptosis.
4th, perhexiline maleate is to the influence into knurl
（1）Stomach cancer and colorectal cancer cell are completed in six orifice plates, after its is adherent, 0 μM, 1 μM and 2 μM maleic acid is added
Perhexiline processes stomach cancer and colon-cancer cell, and observation perhexiline maleate is to HGC27 and MGC803 cells, the and of HCT 116
The influence of DLD-1 cell clonal formations.
Specific method is as follows：
1）Take the logarithm HGC27 and MGC803 cells, HCT 116 and the DLD-1 cells in growth period, with pancreatin by cell dissociation, take
Uniformly it is taped against in six orifice plates per 500, hole cell.
2）After after cell attachment, the culture medium containing various concentrations perhexiline maleate is changed, continue 37 DEG C of incubators
Middle incubated cell.
3）During the macroscopic clone of appearance in orifice plate, terminate culture, suck culture medium, carefully cleaned with PBS.
4）Methyl alcohol uses violet staining after fixing, and air-dries in atmosphere.
5）Taken pictures in inverted microscope.
（2）Experimental result
Result is as shown in Fig. 2 stomach cancer and colorectal cancer cell are by after perhexiline maleate treatment, Clone formation number is obvious
Decline, show that perhexiline can significantly inhibit stomach cancer with colorectal cancer cell into knurl.
The influence that the perhexiline of embodiment 2 is bred to stomach cancer and colorectal cancer cell
1st, experiment material
（1）Medicine：With embodiment 1.
（2）Cancer cell：With embodiment 1.
（3）MTS reagent box purchased in market.
2nd, HGC27 the and MGC803 cells after MTT methods detect that perhexiline maleate is processed, and the Hes of HCT 116
DLD-1 cytoactives
（1）Stomach cancer and colorectal cancer cell are completed in 96 orifice plates, after its is adherent, is added and is contained 0 μM, 5 μM, 10 μM, 20 μM
The medium treatment cell of perhexiline maleate, then detects HGC27 and MGC803 in 24h, 48h, 72h by MTT methods
Cell, HCT 116 and DLD-1 cytoactives.
Specific method is as follows：
1）After HGC27 the and MGC803 cells of exponential phase, HCT 116 and DLD-1 cells are digested with pancreatin, 4 × 10 are taken3
Cell is uniformly taped against in 96 orifice plates.
2）After after cell attachment, the culture medium containing various concentrations perhexiline maleate is changed.
3）After adding medicine 24h, 48h, 72h, by 1:10 ratios add MTS reagent, after 37 DEG C are incubated 2h, are examined with ELIASA
Survey 490nm light absorption values.
（2）Experimental result
Result as shown in figure 3, stomach cancer and colorectal cancer cell are by after perhexiline maleate treatment, under cytoactive is obvious
Drop, shows that perhexiline can significantly inhibit stomach cancer and colorectal cancer cell propagation.
The influence that the perhexiline of embodiment 3 is shifted to stomach cancer and colorectal cancer cell
1st, experiment material
（1）Medicine：With embodiment 1.
（2）Stomach cancer cell：With embodiment 1.
（3）There are pre-coated matrigel and the Transwell cells without pre-coated matrigel.
2nd, after Transwell cells detect that perhexiline maleate is processed, to HGC27 and MGC803 cells, HCT
116 and DLD-1 cell invasions and the influence of migration
（1）Stomach cancer and colorectal cancer cell are completed in six orifice plates, after its is adherent, 0 μM, 3 μM and 4 μM is added（Or 5 μM）
Perhexiline maleate processes stomach cancer cell 48h, adds 0 μM, 4 μM and 6 μM perhexiline maleate treatment colon-cancer cell 48h,
HGC27 and MGC803 cells, HCT 116 and DLD-1 are thin after Transwell cells detect that perhexiline maleate is processed again
The influence that born of the same parents attack and migrate.
Specific method is as follows：
1）After HGC27 the and MGC803 cells of exponential phase, HCT 116 and DLD-1 cells are digested with pancreatin, 6 × 10 are taken5
Cell is uniformly taped against in six orifice plates.
2）After after cell attachment, the culture medium containing various concentrations perhexiline maleate is changed.
3）After adding drug-treated, trypsin digestion cell, after PBS, with the resuspended counting of serum free medium.
4）200 μ l cell suspensions are taken, is respectively 1 × 10 containing cell number5It is added to without pre-coated matrigel and has coating base
The Transwell upper chambers of matter glue, add culture mediums of the 600 μ l containing 100% serum in lower room.
5）Cultured cells 48h in 37 DEG C of incubators, takes out cell, and methyl alcohol is used violet staining, removed with cotton swab after fixing
In upper chamber after residual cells, air-dry in atmosphere.
6）Taken pictures in inverted microscope.
（2）Experimental result
As shown in Figure 4 and Figure 5, stomach cancer and colorectal cancer cell are by after perhexiline maleate treatment, migrating and attacking for result
It is decreased obviously to the cell number in lower room, shows that perhexiline can significantly suppress the migration of stomach cancer and colorectal cancer cell
And invasive ability, and the inhibition is in concentration dependent.
The perhexiline maleate of embodiment 4 and oxaliplatin medication
1st, experiment material
（1）Medicine：Perhexiline maleate, oxaliplatin.
（2）Stomach cancer cell：Gastric carcinoma cells HGC27 and MGC803；Colorectal cancer cell：Human colon cancer cell HCT 116
With human colon adenocarcinoma cell DLD-1.
（3）Apoptosis kit purchased in market.
2nd, experiment packet
（1）Control group：Blank, i.e. stomach cancer and colorectal cancer cell are without any drug-treated.
（2）Independent medication group 1：Stomach cancer and colorectal cancer cell are processed using perhexiline maleate.
（3）Independent medication group 2：Stomach cancer and colorectal cancer cell are processed using oxaliplatin.
（4）Drug combination group：Successively stomach cancer and colorectal cancer cell are processed using oxaliplatin and perhexiline maleate.
3rd, Flow cytometry perhexiline maleate, oxaliplatin and both combinations are to stomach cancer and colorectal cancer cell
The influence of apoptosis
（1）Stomach cancer and colorectal cancer cell are completed in 12 orifice plates, after its is adherent, 0 μM is added（Compare）With 20 μM（Stomach
Cancer）、40μM（Intestinal cancer）Oxaliplatin, 4 μM of perhexiline maleate is added after 24h, both be combined treatment cell 24h,
Then Apoptosis by Flow Cytometry situation is passed through.
Specific method is as follows：
1）After HGC27 the and MGC803 cells of exponential phase, HCT 116 and DLD-1 cells are digested with pancreatin, 1 ~ 2 is taken ×
105Cell is uniformly taped against in 12 orifice plates.
2）After after cell attachment, being replaced with stomach cancer cell is incubated containing the 0 μM and 20 μM culture medium of oxaliplatin；Replacing contains
There is the 0 μM and 40 μM culture medium of oxaliplatin to be incubated colon-cancer cell.Added containing 4 μM of perhexiline maleates after being incubated 24h
Culture medium is incubated 24h jointly.
3）After vitellophag, the method treatment cell according to apoptosis detection kit, Annexin V and PI dyeing is completed
Pass through flow cytomery Apoptosis situation afterwards.
（2）Experimental result
Result is as shown in fig. 6, the percentage shown in Fig. 6 is double-negative for Annexin V and PI（That is survivaling cell）Ratio, piperazine gram
Former times woods or oxaliplatin can kill a certain proportion of stomach cancer and colorectal cancer cell, and the survival of both drug combination groups is thin
Born of the same parents' ratio is substantially reduced.
Result shows, on the basis of oxaliplatin use plus uses perhexiline, can be significantly more relative to independent medication group
The apoptosis of induction stomach cancer and colorectal cancer cell, it is shown that perhexiline and oxaliplatin synergistic combinations are using significantly improving stomach
The therapeutic effect of cancer and colorectal cancer, realizes the therapeutic action of Synergistic.
Claims (9)
1. the application of perhexiline and oxaliplatin combination in terms of the medicine for preventing and treating stomach cancer and/or intestinal cancer is prepared.
2. application according to claim 1, it is characterised in that the intestinal cancer is colorectal cancer.
3. application according to claim 1, it is characterised in that the stomach cancer is the phase stomach cancers of Ι to IV.
4. application according to claim 3, it is characterised in that the stomach cancer is IV phase stomach cancer.
5. application according to claim 2, it is characterised in that the colorectal cancer is the phase colorectal cancers of Ι to IV.
6. application according to claim 5, it is characterised in that the colorectal cancer is IV phase colorectal cancer.
7. application according to claim 1, it is characterised in that the medicine refers to that suppression stomach cancer cell and/or intestinal cancer are thin
The growth of born of the same parents, propagation and/or clonality, suppress the invasion and attack and/or transfer of stomach cancer cell and/or colon-cancer cell, and/or
The medicine of the apoptosis of induction stomach cancer cell and/or colon-cancer cell.
8. application according to claim 7, it is characterised in that the stomach cancer cell be gastric carcinoma cells HGC27 or
MGC803；The colon-cancer cell is human colon cancer cell HCT 116 or human colon adenocarcinoma cell DLD-1.
9. a kind of medicine for preventing and treating stomach cancer and/or intestinal cancer, it is characterised in that include perhexiline or its salt, also include Austria
Husky profit platinum.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710104046.1A CN106860462B (en) | 2017-02-24 | 2017-02-24 | The application of perhexiline and oxaliplatin medication in terms for the treatment of gastric cancer and colorectal cancer |
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| CN201710104046.1A CN106860462B (en) | 2017-02-24 | 2017-02-24 | The application of perhexiline and oxaliplatin medication in terms for the treatment of gastric cancer and colorectal cancer |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021225410A1 (en) * | 2020-05-08 | 2021-11-11 | 연세대학교 산학협력단 | Pharmaceutical composition for brain cancer treatment |
-
2017
- 2017-02-24 CN CN201710104046.1A patent/CN106860462B/en active Active
Non-Patent Citations (3)
| Title |
|---|
| ABDELHAMID BEJI等: "Toward the Prognostic Significance and Therapeutic Potential of HER3 Receptor Tyrosine Kinase in Human Colon Cancer", 《CLIN CANCER RES》 * |
| MIKIKO HAYASHI等: "High Expression of HER3 Is Assocaited with a Decreased Survival in Gastric Cancer", 《CLIN CANCER RES》 * |
| XIU-RONG REN 等: "Perhexiline promotes HER3 ablation through receptor internalization and inhibits tumor growth", 《BREAST CANCER RESEARCH》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021225410A1 (en) * | 2020-05-08 | 2021-11-11 | 연세대학교 산학협력단 | Pharmaceutical composition for brain cancer treatment |
| KR20210136707A (en) * | 2020-05-08 | 2021-11-17 | 연세대학교 산학협력단 | Pharmaceutical composition for treating brain cancer |
| KR102430381B1 (en) * | 2020-05-08 | 2022-08-08 | 연세대학교 산학협력단 | Pharmaceutical composition for treating brain cancer |
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