Cancer Therapy & Radiation Oncology

Post-translational histone modifications can play an important role in the cancer development. Leptin, produced by adipose tissue has been identified as a growth factor in certain hormone related cancers including ovarian cancer. Currently, several groups of scientists are working on synthesizing leptin receptor blockers, and number of leptin receptor antagonist were tested in breast, colon and prostate cancer, suggesting their future use in anticancer therapy. The question arises whether the leptin receptor blockers may also act as inhibitors of HDAC in ovarian cancer. As a model we used the epithelial ovarian cancer (chemoresistant-OVCAR-3 and primary-CaOV-3) and folliculoma (adult –KGN and juvenile- COV434) cell lines. Two antagonists: superactive human leptin antagonist-SHLA and quadruple leptin mutein -LAN 2 (L39A/D40A/F41A/I42A have been applied. Particular cell lines were treated with leptin in a dose of 40 ng/ml (noted in obese women) and antagonist in a dose 1000 ng/mL Effect of blockers on HDACs (1,2,3,4,5,6 7,8,9) gene (real time PCR) and protein expression (western blot) were tested, HDACs expression was higher in OVCAR-3>CaOV-3, and higher in COV434>KGN. Leptin increased HDAC 1, 7 and 9 gene expression only in OVCAR-3, while in granulosa tumour cells increased HDAC 2, 6, 7 in KGN and 9 in COV434. SHLA was the most potent HDACs inhibitor in OVCAR-3 cells and reversed stimulatory effect of leptin on HDAC1, 9 gene, and HDAC4, 5 protein expressions. In granulosa tumor cells, Lan-2 seemed to be most potent inhibitor. Reversed stimulatory effect of leptin on HDAC9 gene expression and HDAC 1, 5 protein expression in COV434 cells in KGN cell line both antagonist reversed stimulatury effect of leptin on HDAC 5, 6, 7. It was concluded that leptin receptor antagonist as HDACs inhibitors should be emerged as an exciting new class of potential anticancer agents. However, histopatological type of cancer should be taken into consideration in the choice of leptin receptor inhibitors.