CN105748468A - Application of verteporfin to preparing anti-ovarian cancer medicine and anti-ovarian cancer medicine - Google Patents
Application of verteporfin to preparing anti-ovarian cancer medicine and anti-ovarian cancer medicine Download PDFInfo
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- CN105748468A CN105748468A CN201610190750.9A CN201610190750A CN105748468A CN 105748468 A CN105748468 A CN 105748468A CN 201610190750 A CN201610190750 A CN 201610190750A CN 105748468 A CN105748468 A CN 105748468A
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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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
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Abstract
The invention belongs to the technical field of tumor treatment, and particularly relates to an application of verteporfin to preparing anti-ovarian cancer medicine and the anti-ovarian cancer medicine.A new effective path is provided for treating of ovarian cancer.An experiment proves that the verteporfin has the obvious anti-ovarian cancer effect; as the verteporfin is ophthalmology clinical medicine at present, the safety of the verteporfin is fully verified, and a new effective means is provided for clinic treatment of ovarian cancer.
Description
Technical field
The invention belongs to oncotherapy technical field, be specifically related to Verteporfin purposes in the medicine preparing ovarian cancer resistance and ovarian cancer resistance medicament.
Background technology
Verteporfin (Verteporfin/VP, trade name: visudyne/Visudyne), it is by QLT optical therapeutic company of the U.S. (QLTPhototherapeutics, and a kind of photosensitizer of developing jointly of ciba vision company (CIBAVisionCorporation) Inc.), on April 13rd, 2000 is by U.S. FDA approval listing, it is a class ophthalmic remedy, is mainly used in the diseases such as treatment senile degeneration of macula (ARMD) clinically.
The chemistry of VP 9-methyl (I) by name and 13-methyl (II) trans-(±)-18-ethylene-4,4a-dihydro-3,4-couple of (carbomethoxy)-4a, 8,14,19-tetramethyl-23H, 25H-benzene porphyrin-9,13-dipropyl, relative molecular mass is 718.79.
The mechanism of action that VP has had is, the VP in circulation, by combining with low density lipoprotein, LDL (LDL), is optionally gathered in choroidal neovascularization (CNV), including neovascular endothelium tissue.Activated by non-thermal energy laser, VP after activation is converted into excited triplet state from ground state, in its triplet, VP or directly initiate photochemical reaction by forming oxygen-derived free radicals, or indirectly start photochemical reaction to draw by delivering energy to ground state oxygen and high reaction singlet oxygen.Two kinds of photochemical reactions occur simultaneously, and limitation destroys vascular endothelial tissue, make endothelial tissue release thrombin, under the effect of leukotriene and cyclooxygenase, cause platelet aggregation, and new vessels is inaccessible, terminates the seepage of blood vessel, treats ARMD.Studies have reported that VP is when without activating, has the effect suppressing HIPPO approach main effects factor Yes associated protein (YAP) activity recently.
Ovarian cancer is one of common three big malignant tumor of female reproductive system, and sickness rate occupy wherein the 3rd, but mortality rate but occupies first of genitals's malignant tumor.Pushing away meter according to American Cancer Society (theAmericanCancerSociety), women's ovarian tumors probability throughout one's life is 1/70 (1.4%).When ovarian cancer patients is made a definite diagnosis, about 2/3 for late period, advanced ovarian cancer after standard care (surgical cytoreduction and the combined chemotherapy based on platinum class) though having 2/3 can reach clinical complete remission (CCR), but wherein 2/3 patient also to be recurred in 5 years.Once recurrence, it is difficult to cure.Defeating ovarian cancer is the ultimate challenge that gynecological tumor doctor currently faces.
Summary of the invention
The technical problem to be solved in the present invention is the treatment a kind of new effective way of offer for ovarian cancer.
This invention address that the technical scheme of above-mentioned technical problem there is provided Verteporfin purposes in the medicine preparing ovarian cancer resistance.
Further, above-mentioned ovarian cancer is ovarian epithelial carcinoma.
The present invention additionally provides the medicine of a kind of ovarian cancer resistance simultaneously, and this medicine is with Verteporfin for main active component, and contains pharmaceutically acceptable adjuvant.
Further, above-mentioned ovarian cancer resistance medicament is possibly together with other ovarian cancer resistance active component.
Further, other the ovarian cancer resistance active component described in above-mentioned ovarian cancer resistance medicament is at least one in tumor chemotherapeutic drug or targeting antibodies class medicine.
Wherein the tumor chemotherapeutic drug described in above-mentioned ovarian cancer resistance medicament is at least one in paclitaxel or cisplatin.
Wherein, above-mentioned ovarian cancer is ovarian epithelial carcinoma.
The present invention apparently provides a kind of method using Verteporfin treatment ovarian cancer, and the method is that the Verteporfin of effective dose is applied to ovarian cancer patients, to reach the purpose for the treatment of.
The beneficial effects of the present invention is, creatively provide Verteporfin purposes in ovarian cancer resistance.By studying, the present invention proves that Verteporfin has obvious ovarian cancer resistance effect.And owing to Verteporfin is a kind of clinical ophthalmology medication, safety is verified fully, therefore provides a kind of new effective means for ovarian cancer clinical treatment, has good application prospect.
Accompanying drawing explanation
The Proliferation Ability of SKOV3 (a), OVCAR3 (b) and OVCAR8 (c) cell is tested by Fig. 1, Verteporfin.Result shows that propagation is had obvious inhibiting effect by it, and presents concentration and time dependence.
Fig. 2, Verteporfin can substantially suppress migration (a) and the invasion and attack (b) of SKOV3, OVCAR3 and OVCAR8 cell.
The impact on the YAP of foundation level and induced levels and the expression of downstream target gene thereof of Fig. 3, Verteporfin.
Result shows: VP substantially suppresses SKOV3, the total YAP of the cell (tYAP) of OVCAR3 and OVCAR8, nucleus YAP (nYAP), the expression (a) of Cytoplasm YAP (cYAP) and phosphorylation YAP (pYAP) albumen；No matter the expression of OVCAR8 cell YAP downstream target gene CCN1 and CCN2 is respectively provided with obvious inhibiting effect presentative time dependency by VP in translation skill (b) or transcriptional level (c)；Verteporfin can also suppress the expression (d) of S1P tYAP, pYAP and the CCN2 induced.
Fig. 4, real-time PCR detect the Verteporfin impact on downstream target gene.Result shows, along with the increase of dosage, target gene CCN1 and the CCN2 in YAP downstream is only played inhibitory action by Verteporfin, and the impact of other important composition molecules of HIPPO approach is less.
Fig. 5, the Verteporfin growth inhibition test result to OA2780 tumor.Zoopery shows, compared with matched group, Verteporfin is inconspicuous to the inhibition of A2780 tumor, it is possible to the rare pass of its endogenous YAP expression.
Fig. 6, the Verteporfin growth inhibition test result to OVCAR8 tumor.Result shows that the OVCAR8 tumor growth to endogenous YAP expression is high has inhibitory action
Fig. 7, Verteporfin can substantially reduce the ascites of lotus OVCAR8 tumor nude mice and be formed.
Mark Ki67 is low at the expression relatively matched group of OVCAR8 tumor Verteporfin treatment group for Fig. 8, propagation, illustrates that Verteporfin can by suppressing the propagation of tumor cell to play antitumaous effect.
Fig. 9, internal real-time PCR assay result demonstrate again that, Verteporfin only affect YAP downstream target gene CCN1 and CCN2 expression and to HIPPO approach to mainly comprise composition influence less.
Detailed description of the invention
The present invention is creatively found that Verteporfin is in the effect with obvious ovarian cancer resistance, can be used for the treatment of ovarian cancer.And the Verteporfin of effective dose is applied to ovarian cancer patients, it is possible to therapeutic purposes.And owing to Verteporfin is a kind of clinical ophthalmology medication, safety is verified fully, therefore Verteporfin is prepared the technical scheme of the medicine of ovarian cancer resistance and is also had good application prospect.
Further, Verteporfin is when using as ovarian cancer resistance medicament, it is also possible to other ovarian cancer resistance active component with the use of, to reaching the better or less effect of side effect.These other ovarian cancer resistance active component is selected from least one in tumor chemotherapeutic drug or targeting antibodies class medicine.Further, other the ovarian cancer resistance active component described in described ovarian cancer resistance medicament is at least one in tumor chemotherapeutic drug or targeting antibodies class medicine.And described tumor chemotherapeutic drug is commonly used as paclitaxel or cisplatin.
Wherein, above-mentioned ovarian cancer is ovarian epithelial carcinoma.
Further investigations have shown that, it is possible have with it suppress YAP protein active in ovarian cancer cell to have certain associating that Verteporfin has the effect of outstanding suppression ovarian cancer, it may be possible to obtain obvious ovarian cancer resistance effect by this effect.
By the following examples technical scheme is described in detail.
The inside and outside ovarian cancer resistance test of embodiment one Verteporfin
EXPERIMENTAL DESIGN and process
1. the different VP concentration (2.5 of Methyl thiazoly tetrazolium assay (MTT) method detection is adopted, 5,10,20 μMs) process the ovarian cancer cell line SKOV3 after certain time, the half-inhibition concentration (IC50) of OVCAR3 and OVCAR8 and cell survival rate, and adopt Hirst (Hoechst) staining detection apoptotic index.
2. adopt and corrode cell (Transwell) technology, monitor ovarian cancer cell invasion and attack under half-inhibition concentration VP effect and transfer ability.
3. A2780 and OVCAR8 ovarian cancer nude mice abdominal cavity Implanted model is set up, it is then split into 4 groups (n=5), respectively blank PBS group, negative control dimethyl sulfoxide (DMSO) group, standard control cisplatin (DDP) group and VP group, thus evaluating the anti-tumor in vivo activity of VP.Wherein VP is first dissolved in DMSO and makes mother solution, then dilutes with the whole dosage PBS of 100mg/kg and note in nude mouse for 200 microlitre abdominal cavities, secondary totally three weeks on every Wendesdays.PBS and DMSO then adopts the dosage identical with VP group, concentration, administering mode and the course for the treatment of.DDP is again by lumbar injection, and dosage is 3mg/kg, every four days once totally 5 times.
4. Immunohistochemical Method (IHC) is adopted to detect the expression of proliferative index Ki67 in A2780 and OVCAR8 tumor tissues after VP processes.
5. real-time PCR and the change of western blotting technique detection HIPPO approach are adopted.
Result explanation
Cell experiment result shows: the propagation of SKOV3, OVCAR3 and OVCAR8 cell is had obvious inhibiting effect (p < 0.05) by VP, and presents concentration and time dependence (referring to Fig. 1).VP can substantially suppress invasion and attack and the transfer ability of SKOV3, OVCAR3 and OVCAR8 cell, p < 0.05 (referring to Fig. 2).VP can substantially suppress SKOV3, the total YAP of OVCAR3 and OVCAR8 cell (tYAP), nucleus YAP (nYAP), the expression (referring to Fig. 3) of Cytoplasm YAP (cYAP) and phosphorylation YAP (pYAP), and suppressing the expression of target gene CCN1 and CCN2 the presentative time dependency in YAP downstream, CCN1 and CCN2 also present identical change (referring to Fig. 4) on transcriptional level.VP can suppress the expression of tYAP, cYAP and the CCN2 albumen under foundation level state and the protein induced state of S1P.Real time PCR results shows, along with the increase of dosage, target gene CCN1 and the CCN2 in YAP downstream is only played inhibitory action by VP, and the impact of other important composition molecules of HIPPO approach is little.
Results of animal: compared with matched group, VP is inconspicuous to the inhibition of the few A2780 tumor of endogenous YAP expression, but the OVCAR8 tumor growth that endogenous YAP expression is high there is is obvious inhibitory action, and the ascites that can substantially reduce nude mice is formed, mark Ki67 is low at the expression relatively matched group of OVCAR8 tumor VP treatment group for propagation, illustrates that VP can by suppressing the propagation of tumor cell to play anticancer effect (referring to Fig. 5, Fig. 6, Fig. 7, Fig. 8).
Internal Real time PCR results demonstrates again that, VP only affects the expression of YAP downstream target gene CCN1 and CCN2 and HIPPO approach is mainly comprised composition influence less (referring to Fig. 9).
To sum up it is concluded that VP has and suppresses the effect of YAP protein active in ovarian cancer cell, and demonstrate obvious inside and outside tumor-inhibiting action by this effect.Owing to VP is a kind of clinical ophthalmology medication, it is expected to the clinical treatment to ovarian cancer provides a kind of new safely and effectively Therapeutic Method.
Claims (7)
1. Verteporfin purposes in the medicine preparing ovarian cancer resistance.
2. purposes according to claim 1, it is characterised in that described ovarian cancer is ovarian epithelial carcinoma.
3. the medicine of ovarian cancer resistance, it is characterised in that: with Verteporfin for main active component, and containing pharmaceutically acceptable adjuvant.
4. medicine according to claim 3, it is characterised in that: possibly together with other ovarian cancer resistance active component.
5. medicine according to claim 4, it is characterised in that: other ovarian cancer resistance active component described is at least one in tumor chemotherapeutic drug or targeting antibodies class medicine.
6. medicine according to claim 5, it is characterised in that: described tumor chemotherapeutic drug is at least one in paclitaxel or cisplatin.
7. the medicine according to any one of claim 3～6, it is characterised in that described ovarian cancer is ovarian epithelial carcinoma.
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| CN201610190750.9A CN105748468A (en) | 2016-03-30 | 2016-03-30 | Application of verteporfin to preparing anti-ovarian cancer medicine and anti-ovarian cancer medicine |
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| CN201610190750.9A CN105748468A (en) | 2016-03-30 | 2016-03-30 | Application of verteporfin to preparing anti-ovarian cancer medicine and anti-ovarian cancer medicine |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111956643A (en) * | 2020-09-15 | 2020-11-20 | 西安交通大学 | Application of verteporfin in preparation of obesity drug |
| CN113461587A (en) * | 2020-03-31 | 2021-10-01 | 中国医科大学附属第一医院 | Small molecule inhibitor YAP1-Y7 aiming at YAP1 and application thereof |
| CN113546076A (en) * | 2020-04-23 | 2021-10-26 | 复旦大学 | Application of verteporfin in preparation of medicine for resisting novel coronavirus SARS-CoV-2 |
| CN114146086A (en) * | 2022-01-21 | 2022-03-08 | 北京市肿瘤防治研究所 | Application of verteporfin in preparation of anti-cancer pain medicine |
-
2016
- 2016-03-30 CN CN201610190750.9A patent/CN105748468A/en active Pending
Non-Patent Citations (4)
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| CHEN QIAN等: "A temporal requirement for Hippo signaling in mammary gland differentiation, growth, and tumorigenesis", 《GENES & DEVELOPMENT》 * |
| KELLY L. MOLPUS等: "Intraperitoneal Photodynamic Therapy of Human Epithelial Ovarian Carcinomatosis in a Xenograft Murine Model", 《CANCER RESEARCH》 * |
| 夏燕: "YAP基因在卵巢肿瘤发生、恶性转移及卵巢癌干细胞中的作用研究", 《中国博士学位论文全文数据库医药卫生科技辑》 * |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113461587A (en) * | 2020-03-31 | 2021-10-01 | 中国医科大学附属第一医院 | Small molecule inhibitor YAP1-Y7 aiming at YAP1 and application thereof |
| CN113461587B (en) * | 2020-03-31 | 2022-07-01 | 中国医科大学附属第一医院 | Small molecule inhibitor YAP1-Y7 aiming at YAP1 and application thereof |
| CN113546076A (en) * | 2020-04-23 | 2021-10-26 | 复旦大学 | Application of verteporfin in preparation of medicine for resisting novel coronavirus SARS-CoV-2 |
| CN113546076B (en) * | 2020-04-23 | 2024-04-30 | 复旦大学 | Application of verteporfin in preparing medicine for resisting novel coronavirus SARS-CoV-2 |
| CN111956643A (en) * | 2020-09-15 | 2020-11-20 | 西安交通大学 | Application of verteporfin in preparation of obesity drug |
| CN114146086A (en) * | 2022-01-21 | 2022-03-08 | 北京市肿瘤防治研究所 | Application of verteporfin in preparation of anti-cancer pain medicine |
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Application publication date: 20160713 |