title: Digitoxin and its synthetic analog MonoD have potent antiproliferative effects on lung cancer cells and potentiate the effects of hydroxyurea and paclitaxel.
abstract: Despite significant advances in the understanding of lung cancer biology, the prognosis of cancer patients remains poor. Part of the failure of anticancer therapy is due to intratumoral heterogeneity in these patients that limits the efficacy of single agents. Therefore, there is an urgent need for new anticancer drugs or drug combination regimens that possess increased activity against all cellular subtypes found within the tumor. In this study, we evaluated the in vitro antiproliferative activity of the cardiac glycosides (CGs) digitoxin and its synthetic analog MonoD on H460 lung cancer cells grown under different culture conditions. The CGs were tested alone in H460 cells under routine culture as well as in cells growing under short (24-72 h) and prolonged serum starvation (7 days) in order to evaluate the activity of drugs on cancer cells under varied degrees of proliferation. Our results showed that both CGs, and MonoD in particular, have potent antiproliferative activity at clinically relevant concentrations against cells in all the tested culture conditions. In contrast, paclitaxel, hydroxyurea and colchicine were only active in cells growing in routine culture conditions, and relatively inactive in serum-starved conditions. Importantly, both CGs were able to potentiate the effect of clinically relevant concentrations of hydroxyurea or paclitaxel in serum-starved conditions. When paclitaxel was used in combination with CGs, the highest antiproliferative effect was obtained when paclitaxel was administered first, followed by either digitoxin or MonoD. Our results indicate that CGs have potential clinical applications in translational oncology especially in combination with other drugs, and warrants further investigation of CGs in more advanced preclinical models of lung cancer.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, VA 23668, USA.
authors.forename: Juan Sebastian
authors.initials: JS
authors.lastname: Yakisich
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, VA 23668, USA.
authors.forename: Neelam
authors.initials: N
authors.lastname: Azad
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, VA 23668, USA.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Venkatadri
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, VA 23668, USA.
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Kulkarni
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, VA 23668, USA.
authors.forename: Clayton
authors.initials: C
authors.lastname: Wright
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, VA 23668, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Kaushik
authors.affiliation: Department of Chemistry, Northeastern University, Boston, MA 02115, USA.
authors.forename: George A
authors.initials: GA
authors.lastname: O'Doherty
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, VA 23668, USA.
authors.forename: Anand Krishnan V
authors.initials: AK
authors.lastname: Iyer
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004074:Digitoxin / Q000494:pharmacology*; D004357:Drug Synergism; D006601:Hexoses / Q000494:pharmacology*; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D006601:Hexoses; C020615:digitoxose; D004074:Digitoxin; D017239:Paclitaxel; D006918:Hydroxyurea