G. V. Georgakis1, N. Charisis1, F. Philanthope1, C. Preece1, M. Talamini1, J. Kim1, A. Sasson1, P. Carino-Thompson1 1Stony Brook University Medical Center,Surgical Oncology,Stony Brook, NY, USA
Introduction: Heated Intraperitoneal Chemotherapy (HIPEC) has been shown to improve outcomes in patients with several diffuse peritoneal cancer, including cancers of colorectal origin. The drugs that have been mainly used during this procedure are mitomycin C (MMC) and oxaliplatin. Since heat shock proteins (HSPs), especially HSP90, have been shown to be adundantly expressed by cancer cells, and their inhibition has been shown to induce apoptosis and cell cycle arrest in both in vitro and in vivo, we hypothesized that addition of the novel HPS90 inhibitor ganetespib, which is well tolerated and currently under clinical investigation, could increase the efficacy of chemotherapy in association with hyperthermia.
Methods: We used two cell lines of colorectal origin (HCT116 and HT29) and we performed proliferation assays with the Cell Counting Kit-8 Cell Proliferation / Cytotoxicity Assay Kit with . Additionally, for molecular studies we perfomed western blots.
Results: HSP90 was fundamentally expressed by both HCT116 and HT29 cells. MMC and ganetespib as monotherapy were found to have an antiproliferative effect in a time and dose manner in HCT116 and HT29 cells. Additionally, hyperthermia at 42C had a similar antiproliferative effect in a time manner. Combination of non lethal doses of MMC and ganetespib had a significant synergistic antiproliferative effect effect on both cell lines, which was more evident at 48 hours.
Conclusion: The HSP90 inhibitor ganetespib in hyperthermic conditions, potentiates the effect of chemotherapy (MMC), and may have a role in cytoreductive surgery and HIPEC.