CN110812356A - Application of losartan in preparation of antitumor drugs - Google Patents
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- CN110812356A CN110812356A CN201911317413.1A CN201911317413A CN110812356A CN 110812356 A CN110812356 A CN 110812356A CN 201911317413 A CN201911317413 A CN 201911317413A CN 110812356 A CN110812356 A CN 110812356A
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
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Abstract
The invention discloses an application of losartan in tumor resistance, which uses losartan to inhibit the combination of Ang II and Ang II type 1 receptors and is responsible for triggering most of RAS-related activities including angiogenesis, cell proliferation and migration, so that losartan can inhibit angiogenesis, cell proliferation and other activities in the tumor interior and the tumor periphery area to directly and indirectly inhibit the growth of tumor cells in two ways (reduce oxygen and nutrition supply).
Description
Technical Field
The invention relates to an anti-tumor drug, in particular to application of losartan in preparation of the anti-tumor drug.
Background
Vascular Endothelial Growth Factor (VEGF), also known as Vascular Permeability Factor (VPF), is a highly specific vascular endothelial cell growth factor that has the effects of promoting vascular permeability increase, extracellular matrix degeneration, vascular endothelial cell migration, proliferation, and angiogenesis. The control of tumor growth by inhibiting angiogenesis, which renders cancer cells unable to grow and spread, has been the direction of cancer biology.
Because cancer cell proliferation requires a switch in the "vascular phenotype" and increases the yield of a number of angiogenic factors, including Vascular Endothelial Growth Factor (VEGF) and factors that stimulate VEGF. The angiotensin system (RAS) is such a system and is involved in blood pressure regulation. The binding of angiotensin ii (ang ii) to the AT1R receptor is the major effector peptide of the angiotensin system, which both increases VEGF and VEGF2R levels and promotes cell proliferation and metabolism. Angiogenesis and the "vascular phenotype" switch are key to tumor growth and spread and this switch is associated with the increase of many angiogenic factors, including Vascular Endothelial Growth Factor (VEGF) and factors that stimulate VEGF, such as the renin angiotensin system.
Losartan is an antihypertensive drug of the angiotensin II receptor Antagonist (ARB) class. The codiin subunit is capable of blocking angiotensin II, a key hormone in the regulation of blood pressure in vivo. The losartan can specifically antagonize angiotensin II AT1 receptor, block the effects of arterial vasoconstriction, sympathetic nerve excitation, increased sensitivity of baroreceptors and the like caused by angiotensin II (ANG II) in circulation and local tissues, powerfully and continuously reduce blood pressure, and reduce systolic pressure and diastolic pressure. Can also relieve left ventricular hypertrophy, inhibit cardiac muscle cell proliferation, delay or reverse cardiac muscle reconstruction, and improve left ventricular function. Has no adverse effect on blood sugar and blood lipid metabolism. It also has effects in improving renal hemodynamics, relieving renal vascular resistance, selectively dilating glomerular arteriole, reducing intraglomerular pressure, reducing albuminuria, increasing renal blood flow and glomerular filtration rate, protecting kidney, and delaying chronic renal insufficiency, especially has reversal effect on diabetic nephropathy. Losartan is not studied as a drug for antitumor therapy, and the existing antitumor chemotherapeutic treatment has serious side effects and may cause the occurrence of cardiovascular diseases such as myocardial ischemia, infarction, heart failure, hypertension, thrombosis and the like. As part of cancer treatment, while these side effects are within an acceptable risk range, they can have a significant impact on patient quality of life and normal treatment progress when receiving other existing chemotherapy, thereby affecting the patient's overall prognosis. This also means that this existing anti-tumor chemotherapy can only be used for a limited period of time before the patient needs to recover. Therefore, the use of losartan as an anticancer drug can control cardiovascular formation, the development and migration of cancer cells, and also contribute to the improvement of cardiovascular side effects of existing chemotherapy.
Disclosure of Invention
In view of the above problems, the present invention provides a new use of losartan for antitumor drugs.
The invention provides an application of losartan in preparation of antitumor drugs.
The invention provides an application of losartan in inhibiting the growth of blood vessels.
The invention provides application of losartan in blocking an Ang II/AT1R pathway.
The tumor comprises one or more of lung cancer, liver cancer, gastric cancer, breast cancer and cervical cancer.
The losartan has the following structural formula
The studies show that the tissue Renin Angiotensin System (RAS) can increase the productivity of Vascular Endothelial Growth Factor (VEGF) by angiotensin II (AngII) type 1 receptor (AT1R) Ang II stabilizes hypoxia inducible factor (HIF-1 α) resulting in an increase in VEGF levels, Ang II acts by its own AT1R promoting proliferation of tumor cells the most different of the existing anti-angiogenic therapies from the therapies proposed by this patent is that the present therapy will employ the existing daily used anti-hypertensive drug Losartan (Losartan) to combat angiogenesis, as Losartan is a drug, so it is well understood that its adverse effects are common and only marginally affecting the quality of life of patients, furthermore, these anti-hypertensive drugs also act on AT1R pathway (regulator of VEGF mediated angiogenesis system) and participate in regulating cell proliferation and cell invasion, thus, it is not necessary to use this therapy only during the therapy, it can be used during the cancer therapy, after the therapy, as a therapy for prolonging the effect of uterine endothelial cell proliferation, after this therapy, it can be used as a mutual inhibition of the endothelial growth factor (AT) in the endometrial cell line expression of the endothelial growth factor in vitro and inhibition of the endothelial cell proliferation of the endothelial growth factor (AT 1) of the therapy of the endometrial growth factor (AT 1-proliferation pathway, thus, it can be used as a mutual inhibition of the in the therapy of the endometrial angiogenesis of the development of endometrial angiogenesis of the therapy of the endometrial angiogenesis of the endometrial cell line (AT 1-endothelial growth factor (AT 1) and the therapy of endometrial angiogenesis of the therapy of the endometrial angiogenesis of the tumor cell line (AT 1-endothelial growth factor (AT 1) and the endometrial angiogenesis of the tumor cell line (AT 1) can be compared to the therapy of endometrial angiogenesis of the therapy of the endometrial angiogenesis of the invention, the invention.
The invention has the advantages that:
the biggest difference between the existing anti-angiogenesis therapy and the therapy proposed by the patent is that the existing daily used anti-hypertension drug Losartan (Losartan) is applied to anti-angiogenesis, and people have fully known adverse reactions because Losartan is a common drug and have little influence on the life quality of patients. In addition, these antihypertensive drugs act on the AT1R pathway (a regulator of the VEGF-mediated angiogenic system) and are implicated in regulating cell proliferation and cell invasion. Thus, there is no need to use this treatment only during the treatment period, it can be used during, after, or as a means of prolonging the survival of the cancer after the treatment is successful. This treatment modality has minimal impact on the quality of life of the patient. Therapeutic agents can act on the AT1R pathway involved in regulating cell proliferation and invasion. Such treatment regimens can be used not only throughout the treatment period, but also to prevent cancer recurrence after successful treatment.
Drawings
Figure 1, angiogenic tissue renin angiotensin system pathway and downstream effects. The red marker represents the site of action of angiotensin receptor inhibitors (ARBs).
FIG. 2, angiotensin II (AngII) promotes the expression of Vascular Endothelial Growth Factor (VEGF) in the endometrial epithelial cancer cell line (ECC-1) compared to control cells, while the AT1R inhibitor, losartan, inhibits the expression of Vascular Endothelial Growth Factor (VEGF).
Fig. 3 demonstrates that angiotensin ii (ang ii) promotes cell proliferation and migration in most cancer cell lines compared to control cells by MTT and wound repair experiments (scratch experiments). Whereas losartan (losartan) showed a significant effect of inhibiting cell proliferation and migration in most of the cell lines tested (P < 0.05).
Detailed Description
The present invention is further illustrated by the following specific examples, which are intended to be illustrative, not limiting and are not intended to limit the scope of the invention.
As shown in fig. 1, losartan is an antihypertensive drug of the angiotensin II receptor Antagonist (ARB) class. Flusartan is able to block angiotensin II, a key hormone in the regulation of blood pressure in vivo. The losartan can specifically antagonize the combination of angiotensin II and angiotensin II AT1 receptors, block the effects of arterial vasoconstriction, sympathetic nerve excitation, increased sensitivity of baroreceptors and the like caused by angiotensin II (ANG II) in circulation and local tissues, powerfully and continuously reduce blood pressure, and reduce systolic pressure and diastolic pressure. Can also relieve left ventricular hypertrophy, inhibit cardiac muscle cell proliferation, delay or reverse cardiac muscle reconstruction, and improve left ventricular function. Has no adverse effect on blood sugar and blood lipid metabolism. It also has effects in improving renal hemodynamics, relieving renal vascular resistance, selectively dilating glomerular arteriole, reducing intraglomerular pressure, reducing albuminuria, increasing renal blood flow and glomerular filtration rate, protecting kidney, and delaying chronic renal insufficiency, especially has reversal effect on diabetic nephropathy. The proposed method can inhibit angiogenesis, cell proliferation and other activities in the tumor and in the tumor peripheral region, so as to directly and indirectly inhibit the growth of tumor cells in two ways (reduce oxygen and nutrition supply).
We have conducted in vitro studies on the expression of the Renin Angiotensin System (RAS) pathway in endometrial cells, observing an endometrial epithelial cancer cell line (ECC-1) which can produce angiotensin ii (angii) and interact with its own AT1Rs (pro-angiogenesis and proliferation).
As shown in FIG. 2, angiogenesis activity was measured using an endometrial cancer cell line (ECC-1), and Vascular Endothelial Growth Factor (VEGF) was a key factor in neovascularization (angiogenesis). We measured the mRNA expression over 48 hours for ECC-1 cells cultured in medium without drug complex (control group Con), 100nM Ang II (Ang II group) and 2uM ARB Losartan (Losartan). We found that AngII significantly promoted VEGF expression as expected since it stimulated the AT1R pathway (P < 0.038). And compared with the control group, losartan (losartan) remarkably inhibits the expression of VEGF in ECC-1 cells, thereby inhibiting signals of angiogenesis (P is 0.002). Therefore, the study principle demonstrated that in endometrial cancer cell lines, drugs that block the ANGII/AT1R pathway inhibit the expression of key angiogenic factors with carcinogenic effects.
FIG. 3 shows that the endometrial cancer cell lines ECC-1, HEC-1, Ishikawa and RL95-2 were used to measure proliferation (cell growth) and migration (important factors for invasion and metastasis) activities. These cells were cultured in medium without drug complex (control group), 100nM Ang II (Ang II group) and 2uM ARB losartan (losartan group) for 48 hours, respectively. We measured proliferation by observing the total cell number by MTT assay and migration by wound repair (scratch assay). We found that Ang II significantly promoted cell proliferation of four cell lines compared to the control group, while Losartan (Losartan) significantly inhibited proliferation of HEC-1, Ishikawa and RL95-2 cell lines and was able to inhibit proliferation of ECC-1 cells to some extent. Ang II significantly promoted cell migration of ECC-1 and HEC-1 cell lines compared to the control group, while Ishikawa and RL95-2 cell migration was not significantly affected and losartan (losartan) was able to inhibit migration of the four cell lines.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (4)
1. The application of losartan in preparing antineoplastic medicines.
2. Use of losartan for inhibiting the growth of blood vessels.
3. The use of claim 1, wherein the tumor comprises one or more of lung cancer, liver cancer, stomach cancer, breast cancer, cervical cancer.
4. The use according to any one of claims 1 to 3, characterized in that losartan has the following structural formula
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101612400A (en) * | 2009-07-22 | 2009-12-30 | 陈志龙 | 1 application of receptor antagonist in antitumor of angiotensin |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101612400A (en) * | 2009-07-22 | 2009-12-30 | 陈志龙 | 1 application of receptor antagonist in antitumor of angiotensin |
Non-Patent Citations (3)
| Title |
|---|
| CHEL HUN CHOI等: ""Angiotensin II type I receptor and miR-155 in endometrial cancers: Synergistic antiproliferative effects of anti-miR-155 and losartan on endometrial cancer cells"", 《GYNECOLOGIC ONCOLOGY》 * |
| 张铭娜等: ""血管紧张素Ⅱ及其Ⅰ型受体与妇科肿瘤"", 《国际妇产科学杂志》 * |
| 谢军: "《全科医学概论与心血管疾病综合诊治新策略》", 31 October 2018 * |
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