Manipulation of metabolic responses enhances SHetA2 efficacy without toxicity in cervical cancer cell lines and xenografts

Objective. The high frequency of cervical cancer recurrence after primary therapy necessitates alternative treatments. High-risk human papillomavirus (HR-HPV) causes cervical cancer and it's continued presence supports elevated metabolism, proliferation and survival of cancer cells. The low-to-no toxicity new investigational drug, SHetA2, counteracts high-risk human papillomavirus (HR-HPV) effects on cell proliferation and survival in cervical cancer cells and xenograft tumors by disrupting heat shock protein 70 chaperone protection of oncogenic proteins. Our objective was to study the involvement of metabolism in SHetA2 effects on cervical cancer cells and tumors. Methods. SHetA2-mediated proteomic and metabolic effects were measured in HR-HPV-positive CaSKi and SiHa and HR-HPV-negative C-33 A cervical cancer cell lines. Combined treatment with 2-deoxyglucose (2-DG) was evaluated in cell culture and SiHa xenografts. Results. SHetA2 inhibited oxidative phosphorylation (OxPhos) and altered levels of proteins involved in metabolism, protein synthesis, and DNA replication and repair. Cervical cancer cells responded by elevating glycolysis. Inhibition of the glycolytic responses using galactose media or 2-DG increased SHetA2 sensitivity of two HR-HPV-positive, but not an HR-HPV-negative cervical cancer cell line. Interaction of 2-DG and SHetA2 was synergistic in HR-HPV positive cell lines in association with augmentation of SHetA2 ATP reduction, but not SHetA2 DNA damage induction. These results were verified in a SiHa xenograft tumor model without evidence of toxicity. Conclusions. Compensatory glycolysis counteracts OxPhos inhibition in SHetA2-treated HR-HPV-positive cervical cancer cell lines. Prevention of compensatory glycolysis with 2-DG or another glycolysis inhibitor has the potential to improve SHetA2 therapy without toxicity.