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 diethyl nitrosamine (DENA) (200 mg/kg, ip),
followed by phenobarbital sodium (0.05%) in drinking water for 18 weeks. At the end of 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 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, Ki67 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 intervention of
Ca+2/PI3K pathway, manifested by ameliorating angiogenesis, apoptosis, proliferation and
metastasis.
Cyclin D1 and Ki-67 expression correlates to tumor staging in tongue squamous cell carcinoma