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Dantrolene Potentiates the Antineoplastic Effect of Sorafenib in Hepatocellular Carcinoma via Targeting Ca +2 /PI3K Signaling Pathway.
- Source :
-
Current molecular pharmacology [Curr Mol Pharmacol] 2021; Vol. 14 (5), pp. 900-913. - Publication Year :
- 2021
-
Abstract
- Background: Hepatocellular carcinoma (HCC) is the 6th prevalent cancer and the 4th leading cause of cancer-related deaths all over the world. A major challenge for sorafenib, the standard chemotherapeutic agent in HCC treatment, is the chemo-resistance.<br />Objective: This study was conducted to evaluate the role of dantrolene as a possible antineoplastic agent in HCC, and in chemo-sensitization of sorafenib via targeting Ca+2/PI3K pathway.<br />Methods: HCC was induced in rats using a single dose of diethylnitrosamine (DENA) (200 mg/kg, ip), followed by phenobarbital sodium (0.05%) in drinking water for 18 weeks. At the end of the 18th week, rats were allocated into 4 groups (10 rats/each), one group was left without treatment (DENA group) and the other three groups were treated with either sorafenib, dantrolene, or their combination for further 4 weeks. One day after the last injection, serum and liver tissues were collected. Liver tissue p53, VEGF, MMP-9, Cyclin D1, PI3K, and, serum AFP were assessed using immunoassay. Hepatic and serum Ca+2 were also computed. Furthermore, Ki-67 was assessed immunohistochemically.<br />Results: Dantrolene exhibited synergistic effect when used in combination with sorafenib compared to either drug alone (p <0.05) through decreasing p53, VEGF, MMP-9, Cyclin D1, and Ki-67. In addition, dantrolene was evidenced to have an inhibitory effect on Ca+2/PI3K pathway that mediates its antineoplastic action when used alone or in combination with sorafenib.<br />Conclusion: Dantrolene exerted antineoplastic effect as well as augmented sorafenib antineoplastic activity via the intervention of Ca+2/PI3K pathway, manifested by ameliorating angiogenesis, apoptosis, proliferation and metastasis.<br /> (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Subjects :
- Animals
Cell Line, Tumor
Cell Proliferation
Dantrolene adverse effects
Phosphatidylinositol 3-Kinases
Rats
Signal Transduction
Sorafenib adverse effects
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Carcinoma, Hepatocellular drug therapy
Carcinoma, Hepatocellular pathology
Liver Neoplasms drug therapy
Liver Neoplasms pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1874-4702
- Volume :
- 14
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Current molecular pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 33573585
- Full Text :
- https://doi.org/10.2174/1874467214666210126110627