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Invest New Drugs. 2019 Jun;37(3):431-440. doi: 10.1007/s10637-018-0643-4. Epub 2018 Jul 30.

Induction of endoplasmic reticulum stress by aminosteroid derivative RM-581 leads to tumor regression in PANC-1 xenograft model.

Author information

1
Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center (CHUL, T4-42), 2705 Laurier Boulevard, Québec, QC, GIV 4G2, Canada.
2
Department of Anatomo-Pathology, CHU de Québec - Université Laval, Québec, QC, GIV 4G2, Canada.
3
Faculty of Pharmacy, Université Laval, Québec, QC, GIV OA6, Canada.
4
Endocrinology and Nephrology Unit, CHU de Québec-Research Center (CHUL, T4-13), Québec, QC, GIV 4G2, Canada.
5
Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center (CHUL, T4-42), 2705 Laurier Boulevard, Québec, QC, GIV 4G2, Canada. donald.poirier@crchul.ulaval.ca.
6
Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, QC, GIV OA6, Canada. donald.poirier@crchul.ulaval.ca.

Abstract

The high fatality and morbidity of pancreatic cancer have remained almost unchanged over the last decades and new clinical therapeutic tools are urgently needed. We determined the cytotoxic activity of aminosteroid derivatives RM-133 (androstane) and RM-581 (estrane) in three human pancreatic cancer cell lines (BxPC3, Hs766T and PANC-1). In PANC-1, a similar level of antiproliferative activity was observed for RM-581 and RM-133 (IC50 = 3.9 and 4.3 μM, respectively), but RM-581 provided a higher selectivity index (SI = 12.8) for cancer cells over normal pancreatic cells than RM-133 (SI = 2.8). We also confirmed that RM-581 induces the same ER stress-apoptosis markers (BIP, CHOP and HERP) than RM-133 in PANC-1 cells, pointing out to a similar mechanism of action. Finally, these relevant in vitro results have been successfully translated in vivo by testing RM-581 using different doses (10-60 mg/kg/day) and modes of administration in PANC-1 xenograft models, which have led to tumor regression without any sign of toxicity in mice (animal weight, behavior and histology). Interestingly, RM-581 fully reduced the pancreatic tumor growth when administered orally in mice.

KEYWORDS:

Aminosteroid; Endoplasmic reticulum stress aggravator; Mouse xenograft; PANC-1 cells; Pancreatic cancer

PMID:
30062573
DOI:
10.1007/s10637-018-0643-4
[Indexed for MEDLINE]

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