CN105687171A - New application of aminoquinol - Google Patents
New application of aminoquinol Download PDFInfo
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- CN105687171A CN105687171A CN201610059096.8A CN201610059096A CN105687171A CN 105687171 A CN105687171 A CN 105687171A CN 201610059096 A CN201610059096 A CN 201610059096A CN 105687171 A CN105687171 A CN 105687171A
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- rafoxanide
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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Abstract
The invention discloses a new application of Rafoxanide. The influence of Rafoxanide to the skin cancer cell lines A375 and A431 is tested through a series of experiments, and the experiments indicate that the Rafoxanide is a target CDK4/6 inhibitor and can increase the number of cells of A375 and A431 stagnating in the G1 stage and reduce the number of the cells in the S stage; the apoptosis rate of A375 and A431 can be increased; the protein expression of the CDK 4/6, cyclinD and pho-CDK4/6 of the signal channel in the G1 stage of a cell cycle can be inhibited, a skin cancer-resistant effect is realized, and thus, the Rafoxanide can be used for preparing anti-cancer medicines for treating skin cancer; and since the Rafoxanide is a medicine resisting parasitic diseases already registered by FDA, the later clinical experiment cost is reduced, the medicine development time is shortened, and the cost and time for developing a new anti-cancer medicine are greatly saved.
Description
Technical field
The present invention relates to field of medicaments, specifically the new application of a kind of Rafoxanide。
Background technology
Cell cycling disorder is the mark that malignant tumor is formed, and the activation of cell cycle protein dependent kinase (CDKs) and inactivation maintain each phase of cell cycle to carry out in order。CDK4,6 is the regulatory factor that cell cycle G1 phase early stage is crucial, suppress cell cycle protein dependent kinase CDK4,6 hypertrophy that can suppress tumor cell, it it is a good tumour medicine target spot, so filtering out cyclin-dependent kinase CDK4 capable of inhibiting cell, the medicine of 6 activity can suppress the hypertrophy of tumor cell, plays effect of anti-skin carcinoma；Not good anti-skin carcinoma chemotherapeutics clinically, and anticancer chemotherapeutic agent side effect clinically is strong, so the chemotherapeutics used clinically at present uses very limited, therefore finds novel good anti-skin carcinoma medicament extremely urgent。
Summary of the invention
It is an object of the invention to provide a kind of Rafoxanide for preparing the new application for the treatment of skin carcinoma medicine, with the problem solving to propose in above-mentioned background technology。
For achieving the above object, the present invention provides following technical scheme:
The new application of a kind of Rafoxanide, described Rafoxanide is target spot CDK4/6 inhibitor, has anti-skin carcinoma effect, and Rafoxanide is for preparing the cancer therapy drug for the treatment of skin carcinoma。
As the further scheme of the present invention: skin cancer cell system A375 and A431 is had anticancer effect by described Rafoxanide, with 3 μMs/L, 10 μMs/L, after the Rafoxanide of 30 μMs/L concentration disturbs skin cancer cell system A375 and A431, presentative time is 24h, 48h, 72h respectively, and display presentative time and dose-dependent inhibition A375 and A431 increase effect。
As the present invention further scheme: by 3 μMs/L of Flow cytometry, 10 μMs/L, Rafoxanide disturbs cell cycle distribution situation after skin cancer cell system A375 and A431 under 30 μMs/L concentration conditions, presentative time is respectively 6h, 12h, 24h, Rafoxanide adds the cell quantity being stuck in the G1 phase, and presentative time and dose dependent have the trend of increase, P < 0.05, along with the increase of G1 phase cell quantity, S phase cell quantity reduces。
As the present invention further scheme: by Flow Cytometry detect 3 μMs/L, 10 μMs/L, Rafoxanide disturbs apoptosis quantity after skin cancer cell system A375 and A431 under 30 μMs/L concentration conditions, presentative time respectively 12h, 24h, 36h, Rafoxanide add the apoptosis quantity of cell, display presentative time and dose dependent have the trend of increase, P < 0.05。
As the present invention further scheme: disturb skin cancer cell system A375 and A431 with Rafoxanide, by Western experiment detection and cell cycle G1 phase signaling pathway protein expression, after disturbing skin cancer cell system A375 and A431 with Rafoxanide, exchange the CDK2 of ganglion cell's G1 cycle, signal path phase, 4,6, the situation of change of cyclinD, pho-CDK4/6 expressing quantity detects；Its CDK4 after result display Rafoxanide interference skin cancer cell system A375 and A431,6, cyclinD, pho-CDK4 and pho-CDK6 expressing quantity presents dose dependent downward trend, CDK2 expressing quantity is unchanged, and Rafoxanide is inhibited to CDK4/6。
Compared with prior art, the invention has the beneficial effects as follows: the present invention is by the series of experiments test Rafoxanide impact on skin cancer cell system A375 and A431, show that Rafoxanide is target spot CDK4/6 inhibitor, A375 and A431 can be increased and be stuck in the cell quantity of G1 phase, reduce S phase cell quantity；A375 and A431 apoptosis rate can be improved；The CDK4 of cell cycle G1 phase signal path can be suppressed, 6, cyclinD, pho-CDK4/6 protein expression, there is anti-skin carcinoma effect, therefore, Rafoxanide can be used for preparing the cancer therapy drug for the treatment of skin carcinoma；Due to the Rafoxanide medicine sick for parasiticide registered by FDA, therefore shorten the clinical experiment cost in later stage and the time of drug development, be greatly saved cost and the time of one new cancer therapy drug of exploitation。
Accompanying drawing explanation
Fig. 1 is that in the present invention, variable concentrations Rafoxanide affects A375 cell proliferation curve chart。
Fig. 2 is that in the present invention, variable concentrations Rafoxanide affects A431 cell proliferation curve chart。
Fig. 3 is that in the present invention, variable concentrations Rafoxanide difference presentative time affects A375 cell proliferation curve chart。
Fig. 4 is that in the present invention, variable concentrations Rafoxanide difference presentative time affects A431 cell proliferation curve chart。
Fig. 5 be in the present invention variable concentrations Rafoxanide difference presentative time A375 at the cell quantity change curve of G1 phase。
Fig. 6 be in the present invention variable concentrations Rafoxanide difference presentative time A431 at the cell quantity change curve of G1 phase。
Fig. 7 is the cell cycle distribution bar diagram that in the present invention, variable concentrations Rafoxanide affects A375。
Fig. 8 is the cell cycle distribution bar diagram that in the present invention, variable concentrations Rafoxanide affects A431。
Fig. 9 is the apoptosis number change curve chart of variable concentrations Rafoxanide difference presentative time A375 in the present invention。
Figure 10 is the apoptosis number change curve chart of variable concentrations Rafoxanide difference presentative time A431 in the present invention。
Figure 11 is that in the present invention, variable concentrations Rafoxanide suppresses CDK2,4,6, cyclinD, pho-CDK4 and pho-CDK6 protein expression design sketch in A375 and A431。
Figure 12 is that in the present invention, variable concentrations Rafoxanide suppresses CDK2 protein expression bar diagram in A375 and A431。
Figure 13 is that in the present invention, variable concentrations Rafoxanide suppresses cyclinD protein expression bar diagram in A375 and A431。
Figure 14 is that in the present invention, variable concentrations Rafoxanide suppresses CDK6 protein expression bar diagram in A375 and A431。
Figure 15 is that in the present invention, variable concentrations Rafoxanide suppresses pro-CDK6 protein expression bar diagram in A375 and A431。
Figure 16 is that in the present invention, variable concentrations Rafoxanide suppresses pro-CDK4 protein expression bar diagram in A375 and A431。
Figure 17 is that in the present invention, variable concentrations Rafoxanide suppresses CDK4 protein expression bar diagram in A375 and A431。
Detailed description of the invention
Below in conjunction with detailed description of the invention, the technical scheme of this patent is described in more detail。
The new application of a kind of Rafoxanide, described Rafoxanide is target spot CDK4/6 inhibitor, has anti-skin carcinoma effect, and Rafoxanide is for preparing the cancer therapy drug for the treatment of skin carcinoma。
The determination experiment of this new application comprises the following steps:
1) filter out candidate's CDK4/6 inhibitor of anti-skin carcinoma for target spot CDK4/6 with computer idock software:
It is analyzed from 4,914 medicines in ZINC drug data base that include under dbap and fda catalogue of FDA certification and is ranked up according to the strength of affinity value of binding, therefrom find out and buy 9 the highest compounds of giving a mark and carry out next step experiment；They are Lifibrate, Nizofenone, fumarate, Chloracyzine, adafenoxate, Cloricromene, Sulconazole, nitrate, Rafoxanide respectively；
2) candidate inhibitor screened by the following laboratory vivo and vitro experimental verification pin first step:
2.1) MTT testing sieve finds the compound R afoxanide not reported that IC50 is minimum:
First checked for the anticancer effect of 9 compounds by MTT experiment, skin cancer cell system A375 and A431 is all had anticancer effect by these nine compounds respectively；Go out its IC50 value by graphpadprime5 computed in software, the IC50 value that relatively each compound is corresponding, thus filter out maximally effective compound R afoxanide, A375IC50 be 0.973 μM/L, A431IC50 be 1.05 μMs/L；By 3 μMs/L, 10 μMs/L, Rafoxanide disturbs skin cancer cell system A375 and A431 under 30 μMs/L concentration conditions, presentative time is 24h, 48h, 72h, and display presentative time and dose-dependent inhibition A375 and A431 increase effect；As Figure 1-4；
2.2) Rafoxanide is carried out cell cycle detection
In order to observe the Rafoxanide inhibition to skin cancer cell, by by Flow cytometry at 3 μMs/L, 10 μMs/L, cell cycle distribution situation after Rafoxanide interference skin cancer cell A375 and A431 when 30 μMs/L variable concentrations, presentative time is 6h, 12h, 24h, Rafoxanide greatly adds the cell quantity being stuck in the G1 phase, and presentative time (24h, 48h, 72h) and dosage (3 μMs/L, 10 μMs/L, 30 μMs/L) dependency increase trend, P < 0.05, result shows along with the increase of G1 phase cell quantity, S phase cell quantity reduces；As viewed in figures 5-8；
2.3) Rafoxanide is carried out apoptosis detection
By apoptosis quantity after Flow Cytometry detection Rafoxanide interference skin cancer cell A375 and A431, Rafoxanide greatly adds the apoptosis quantity of cell, and the trend that presentative time 12h, 24h, 36h and dosage (3 μMs/L, 10 μMs/L, 30 μMs/L) dependency increase, P < 0.05, as shown in figs. 9-10；
2.4) after disturbing skin cancer cell A375 and A431 with Rafoxanide, by Western experiment detection and cell cycle G1 signaling pathway protein expression；After Rafoxanide disturbs skin cancer cell system A375 and A431 cell, observe the CDK2 regulating cell cycle G1 phase signal path, 4,6, the situation of change of cyclinD, pho-CDK4/6 expressing quantity, tested by Westernblotting, after Rafoxanide disturbs skin cancer cell, observe and regulate cell cycle G1 phase signaling pathway protein CDK2,4,6, cyclinD, pho-CDK4/6 expression；Result display Rafoxanide disturbs its CDK4 after skin cancer cell A375 and A431,6, cyclinD, pho-CDK4 and pho-CDK6 expressing quantity present dose dependent downward trend, CDK2 expressing quantity is unchanged, as shown in figures 11-17。
More than experiments show that, Rafoxanide is inhibited to CDK4/6, and skin cancer cell system A375 and A431 is had inhibition, has strong anti-skin carcinoma effect, and therefore Rafoxanide can be used for preparing the cancer therapy drug for the treatment of skin carcinoma；Due to the Rafoxanide medicine sick for parasiticide registered by FDA, therefore substantially reduce clinical experiment cost and the drug development time in later stage, save cost and the time of one new cancer therapy drug of exploitation；Its application value is notable。
Above the better embodiment of this patent is explained in detail, but this patent is not limited to above-mentioned embodiment, in the ken that one skilled in the relevant art possesses, it is also possible to make a variety of changes under the premise without departing from this patent objective。
Claims (5)
1. the new application of a Rafoxanide, it is characterised in that described Rafoxanide is target spot CDK4/6 inhibitor, has anti-skin carcinoma effect, and Rafoxanide is for preparing the cancer therapy drug for the treatment of skin carcinoma。
2. the new application of Rafoxanide according to claim 1, it is characterized in that, skin cancer cell system A375 and A431 is had anticancer effect by described Rafoxanide, with 3 μMs/L, 10 μMs/L, after the Rafoxanide of 30 μMs/L concentration disturbs skin cancer cell system A375 and A431, presentative time is 24h, 48h, 72h respectively, and display presentative time and dose-dependent inhibition A375 and A431 increase effect。
3. the new application of Rafoxanide according to claim 1, it is characterized in that, by 3 μMs/L of Flow cytometry, 10 μMs/L, Rafoxanide disturbs cell cycle distribution situation after skin cancer cell system A375 and A431 under 30 μMs/L concentration conditions, presentative time is respectively 6h, 12h, 24h, Rafoxanide adds the cell quantity being stuck in the G1 phase, and presentative time and dose dependent have the trend of increase, P < 0.05, along with the increase of G1 phase cell quantity, S phase cell quantity reduces。
4. the new application of Rafoxanide according to claim 1, it is characterized in that, by Flow Cytometry detect 3 μMs/L, 10 μMs/L, Rafoxanide disturbs apoptosis quantity after skin cancer cell system A375 and A431 under 30 μMs/L concentration conditions, presentative time respectively 12h, 24h, 36h, Rafoxanide add the apoptosis quantity of cell, display presentative time and dose dependent have the trend of increase, P < 0.05。
5. the new application of Rafoxanide according to claim 1, it is characterized in that, skin cancer cell system A375 and A431 is disturbed with Rafoxanide, by Western experiment detection and cell cycle G1 phase signaling pathway protein expression, after disturbing skin cancer cell system A375 and A431 with Rafoxanide, exchange CDK2, the 4,6 of ganglion cell's G1 cycle, signal path phase, the situation of change of cyclinD, pho-CDK4/6 expressing quantity detects；Its CDK4 after result display Rafoxanide interference skin cancer cell system A375 and A431,6, cyclinD, pho-CDK4 and pho-CDK6 expressing quantity presents dose dependent downward trend, CDK2 expressing quantity is unchanged, and Rafoxanide is inhibited to CDK4/6。
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| CN201610059096.8A CN105687171A (en) | 2016-01-28 | 2016-01-28 | New application of aminoquinol |
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| CN201610059096.8A CN105687171A (en) | 2016-01-28 | 2016-01-28 | New application of aminoquinol |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105687172A (en) * | 2016-03-04 | 2016-06-22 | 中国科学院上海药物研究所 | Application of rafoxanide and closantel in preparing anti-tumor drugs |
| CN110123799A (en) * | 2018-02-09 | 2019-08-16 | 中国科学院上海药物研究所 | Rafoxanide application in preparation of anti-tumor drugs |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004006906A2 (en) * | 2002-07-15 | 2004-01-22 | Combinatorx, Incorporated | Methods for the treatment of neoplasms |
| CN102834116A (en) * | 2009-09-21 | 2012-12-19 | 杜克大学 | Treatment of WNT/frizzled-related diseases |
| CN104936586A (en) * | 2012-08-06 | 2015-09-23 | 生命与大脑有限公司 | Niclosamide and its derivatives for use in the treatment of solid tumors |
-
2016
- 2016-01-28 CN CN201610059096.8A patent/CN105687171A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004006906A2 (en) * | 2002-07-15 | 2004-01-22 | Combinatorx, Incorporated | Methods for the treatment of neoplasms |
| CN102834116A (en) * | 2009-09-21 | 2012-12-19 | 杜克大学 | Treatment of WNT/frizzled-related diseases |
| CN104936586A (en) * | 2012-08-06 | 2015-09-23 | 生命与大脑有限公司 | Niclosamide and its derivatives for use in the treatment of solid tumors |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105687172A (en) * | 2016-03-04 | 2016-06-22 | 中国科学院上海药物研究所 | Application of rafoxanide and closantel in preparing anti-tumor drugs |
| CN105687172B (en) * | 2016-03-04 | 2021-02-12 | 中国科学院上海药物研究所 | Application of rafoxanide and closantel in preparing antitumor drugs |
| CN110123799A (en) * | 2018-02-09 | 2019-08-16 | 中国科学院上海药物研究所 | Rafoxanide application in preparation of anti-tumor drugs |
| CN110123799B (en) * | 2018-02-09 | 2022-02-15 | 中国科学院上海药物研究所 | Application of rafoxanide in preparation of antitumor drugs |
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Application publication date: 20160622 |