SHetA2 Increases the Activity of Palbociclib in Cervical Cancer in vitro and in vivo

Abstract

Introduction Cervical cancer is caused by high-risk human papillomavirus (HPV) and treated with conventional chemotherapy combined with surgery and/or radiation. HPV oncoproteins increase retinoblastoma (Rb) phosphorylation by cyclin D1/cyclin dependent kinase (CDK)4/6 complexes and cellular proliferation. We hypothesized that cyclin D1 degradation by the SHetA2 drug in combination with palbociclib inhibition of CDK4/6 activity synergistically reduces Rb phosphorylation and inhibits cervical cancer growth. Methods The effects of these drugs, alone, and in combination, were evaluated in cervical cancer cell lines using cell culture, western blots and ELISA, and in a SiHa xenograft model. Endpoints were compared by isobolograms, ANOVA, and Chi-Square. Results SHetA2 and palbociclib acted synergistically in three cervical cell lines (CI <0.5) in association with reduced Rb phosphorylation. Both drugs significantly reduced Rb phosphorylation and growth of SiHa xenograft tumors as single agents and acted additively when combined, with no evidence of toxicity. SHetA2, but not palbociclib, reduced cyclin D1 in cell cultures and tumors. Dilated CD31-negative blood vessels adjacent to, or within, areas of necrosis and apoptosis were observed in all drug-treated tumors. Conclusions The drug combination was synergistic in vitro and significantly effective in vivo. The mechanism of synergy appears to involve inhibition of Rb phosphorylation.