title: The Aminosteroid Derivative RM-133 Shows In Vitro and In Vivo Antitumor Activity in Human Ovarian and Pancreatic Cancers.
abstract: Ovarian and pancreatic cancers are two of the most aggressive and lethal cancers, whose management faces only limited therapeutic options. Typically, these tumors spread insidiously accompanied first with atypical symptoms, and usually shift to a drug resistance phenotype with the current pharmaceutical armamentarium. Thus, the development of new drugs acting via a different mechanism of action represents a clear priority. Herein, we are reporting for the first time that the aminosteroid derivative RM-133, developed in our laboratory, displays promising activity on two models of aggressive cancers, namely ovarian (OVCAR-3) and pancreatic (PANC-1) cancers. The IC50 value of RM-133 was 0.8 μM and 0.3 μM for OVCAR-3 and PANC-1 cell lines in culture, respectively. Based on pharmacokinetic studies on RM-133 using 11 different vehicles, we selected two main vehicles: aqueous 0.4% methylcellulose:ethanol (92:8) and sunflower oil:ethanol (92:8) for in vivo studies. Using subcutaneous injection of RM-133 with the methylcellulose-based vehicle, growth of PANC-1 tumors xenografted to nude mice was inhibited by 63%. Quite interestingly, RM-133 injected subcutaneously with the methylcellulose-based or sunflower-based vehicles reduced OVCAR-3 xenograft growth by 122% and 100%, respectively. After the end of RM-133 treatment using the methylcellulose-based vehicle, OVCAR-3 tumor growth inhibition was maintained for ≥ 1 week. RM-133 was also well tolerated in the whole animal, no apparent sign of toxicity having been detected in the xenograft studies.
authors.affiliation: Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec-Research Center, Québec, Québec, Canada.|Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, Québec, Canada.
authors.forename: Lucie Carolle
authors.initials: LC
authors.lastname: Kenmogne
authors.affiliation: Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec-Research Center, Québec, Québec, Canada.
authors.forename: Diana
authors.initials: D
authors.lastname: Ayan
authors.affiliation: Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec-Research Center, Québec, Québec, Canada.
authors.forename: Jenny
authors.initials: J
authors.lastname: Roy
authors.affiliation: Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec-Research Center, Québec, Québec, Canada.
authors.forename: René
authors.initials: R
authors.lastname: Maltais
authors.affiliation: Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec-Research Center, Québec, Québec, Canada.|Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, Québec, Canada.
authors.forename: Donald
authors.initials: D
authors.lastname: Poirier
mesh_terms: D000736:Androstenes / Q000097:blood / Q000627:therapeutic use* / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000627:therapeutic use* / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014183:Transplantation, Heterologous
chemical_list: D000736:Androstenes; D000970:Antineoplastic Agents; C000594943:RM-133 aminosteroid