The high fatality pancreatic cancer morbidity has remained almost unchanged over the last decades and new clinical therapeutic tools are urgently needed. Using classic and solid-phase synthesis strategies, we firstly synthesized a series of aminosteroid derivatives that showed cytotoxic activities in various cancer cell lines. Considering the potential of this family of estrane derivatives, we next evaluated the anti-pancreatic cancer activity of the representative compound RM-581. Thus, we measured 75, 60 and 73% of cytotoxic activity for RM-581 at 5 µM in three pancreatic cancer cell lines (BxPC3, Hs766T and PANC-1) representing three stages (early, metastatic and late) of the disease. Under the same conditions, RM-581 has been shown to be more cytotoxic than a series of leading clinical chemotherapeutic drugs. From the IC50 values in PANC-1 cancer cells (3.9 µM) and pancreatic primary normal cells (IC50 = 50 µM), we calculated a selectivity index of 12.8. We also confirmed that RM-581 induces endoplasmic reticulum (ER) stress-apoptosis markers (BIP, CHOP and HERP) in PANC-1 cells, pointing out to an aggravation of ER stress leading to apoptosis. These relevant in vitro results have been next successfully translated in vivo by testing RM-581 using different modes of administration and doses (10 mg/kg/d/intraperitoneal, 60 mg/kg/d/subcutaneous and 60 mg/kg/d/oral) in human PANC-1 xenograft model, which have all led to tumor regression without any sign of toxicity in mice (animal weight, behavior, and histology analysis of organs). Interestingly, the estrane derivative RM-581 has been proven to be an active anticancer molecule that can be administered orally. Altogether, these results qualified RM-581 as a valuable preclinical candidate to be further evaluated in a pancreatic cancer clinical phase 1 trial.

Estrane derivatives induce endoplasmic reticulum stress leading to selective cytotoxicity in pancreatic cancer cells and to tumor regression in PANC-1 xenograft model

256th National Meeting (2018)

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