Dantrolene Potentiates the Antineoplastic Effect of Sorafenib in Hepatocellular Carcinoma via Targeting Ca⁺²/PI3K Signaling Pathway

Title:Dantrolene Potentiates the Antineoplastic Effect of Sorafenib in Hepatocellular Carcinoma via Targeting Ca⁺²/PI3K Signaling Pathway

Volume: 14

Author(s): Sherin Zakaria, Abeer Ansary*, Nabil M. Abdel-Hamid and Mamdouh M. El-Shishtawy*

Affiliation:

• Department of Biochemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516,Egypt

• Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516,Egypt

Keywords: Hcc, dena, sorafenib, dantrolene sodium, ca+2, pi3k.

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.

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.

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.

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.

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.

Cite this article as:

Zakaria Sherin , Ansary Abeer *, Abdel-Hamid M. Nabil and El-Shishtawy M. Mamdouh*, Dantrolene Potentiates the Antineoplastic Effect of Sorafenib in Hepatocellular Carcinoma via Targeting Ca⁺²/PI3K Signaling Pathway, Current Molecular Pharmacology 2021; 14 (5) . https://dx.doi.org/10.2174/1874467214666210126110627