The Aminosteroid Derivative RM-133 Shows In Vitro and In Vivo Antitumor Activity in Human Ovarian and Pancreatic Cancers

• Published in: PloS one Vol. 10; no. 12; p. e0144890
• Main Authors: Kenmogne, Lucie Carolle, Ayan, Diana, Roy, Jenny, Maltais, René, Poirier, Donald
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.12.2015; Public Library of Science (PLoS)
• Subjects: Androgens; Androstenes - blood; Androstenes - therapeutic use; Androstenes - toxicity; Animal models; Animals; Antibiotics; Anticancer properties; Antineoplastic Agents - blood; Antineoplastic Agents - therapeutic use; Antineoplastic Agents - toxicity; Antitumor activity; Apoptosis; Biocompatibility; Cancer therapies; Cell culture; Cell cycle; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemical synthesis; Chemistry; Chemotherapy; Dosage and administration; Drug abuse; Drug development; Drug resistance; Drug therapy; Endocrinology; Ethanol; Female; Humans; In vivo methods and tests; Laboratories; Leukemia; Medical prognosis; Medicine; Methylcellulose; Mice; Mice, Inbred BALB C; Mice, Nude; Nephrology; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - pathology; Pancreas; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - pathology; Patient outcomes; Penicillin; Pharmaceutical sciences; Pharmacology; Phenotypes; Steroids (Drugs); Sunflower oil; Toxicity; Transplantation, Heterologous; Tumors; Vehicles; Womens health; Xenografts; Xenotransplantation; Canada
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0144890

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.