Potentiated antitumor effects of the combination treatment with statins and pamidronate in vitro and in vivo.
The aim of the present study was to examine the potential antitumor activity of lovastatin and other statins together with pamidronate, a second generation bisphosphonate (BP), against tumor cell lines. Cytostatic/cytotoxic effects were measured using crystal violet assay. Regulation of the cell cycle and induction of apoptosis were evaluated using flow cytometry and Western blotting, migration of tumor cells was measured in a scratch wound assay and their invasiveness was measured with a Matrigel-invasion assay. Antitumor effects of the combination treatment were evaluated in a murine PANC 02 pancreatic adenocarcinoma model. Combination of pamidronate and lovastatin produced potentiated cytostatic/cytotoxic effects against breast and pancreatic cancer cell lines. The combination was also effective in inhibition of tumor cell adhesion to collagen IV and fibronectin and interfered with migration and invasiveness of tumor cells. Neither pamidronate nor lovastatin alone affected tumor growth in mice but the combination treatment resulted in retardation of tumor growth and prolongation of mouse survival. The combination of statins and pamidronate, a second generation bisphosphonate, demonstrates promising antitumor effects at doses readily achievable in patients. This combination holds promise for future clinical studies.
Issat
Tadeusz
T
Department of Immunology, Center of Biostructure, The Medical University of Warsaw, 02-097 Warsaw, Poland.
Nowis
Dominika
D
Legat
Magdalena
M
Makowski
Marcin
M
Klejman
Marcin P
MP
Urbanski
Jakub
J
Skierski
Janusz
J
Koronkiewicz
Miroslawa
M
Stoklosa
Tomasz
T
Brzezinska
Agnieszka
A
Bil
Jacek
J
Gietka
Jan
J
Jakóbisiak
Marek
M
Golab
Jakub
J
D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008148:Lovastatin / Q000494:pharmacology*; D051379:Mice; D000077268:Pamidronate; D010190:Pancreatic Neoplasms / Q000188:drug therapy*
D004164:Diphosphonates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D000077268:Pamidronate