Antitumor and apoptosis promoting properties of atorvastatin, an inhibitor of HMG-CoA reductase, against Dalton's Lymphoma Ascites tumor in mice.
Epidemiological and experimental data indicate that high body fat or high dietary fat can be ascribed to the induction of human cancers. Increased level of products of lipid peroxidation and cholesterol-enriched lipid domains in the plasma membrane can favorthe malignant transformation of cells. An effective chemopreventive agent with hypolipaedemic effect will be worthwhile to intervene early in the process of carcinogenesis to eliminate the pre-malignant cells. Apoptotic promoting and antitumor activities of a HMG-Co A reductase inhibitor, atorvatstain were investigated. The antitumor activity was evaluated using Daltons' Lymphoma Ascites (DLA) cell line transplanted ascites tumor model in mice. Proapoptotic activity was evaluated in DLA cell line induced ascites animals after the treatment of atorvastatin (4 and 16 mg/kg, i.p). Apoptosis was analyzed morphologically by staining with giemsa and biochemically by observing the laddering of DNA in agarose gel electrophoresis. In vitro short term cytotoxic activity of atorvatstain was studied by trypan blue dye exclusion method. Doxorubicin was used as the reference standard. Atorvastatin significantly (P < 0.01) inhibited the ascites tumor growth at 16 mg/kg body wt (i.p). The percent increase in life span (%ILS) in the 16 mg/kg treated group was 41.1%. Single dose of atorvastatin (16 mg/kg body wt) was also effective to promote the apoptosis of DLA cells in the ascites tumor bearing mice that was evident from the multiple fragmentation of DNA in agarose gel electrophoresis. Further the morphological analysis of DLA cells aspirated from the atorvastatin treated ascites tumor bearing animals showed 36.34 +/- 6.78% apoptotic cells compared to the control animals (10.50 +/- 3.53%). Concentration of atorvastatin required for the 50% of the cytotoxicity was 30 +/- 2 microg/ml. Results of the study concluded that the antitumor activity of atorvastatin may be due to its proapoptotic and cytotoxic activities. These pleiotropic activities of the hypolipedaemic drug atorvastatin suggest its possible use as a cancer chemopreventive agent.
Ajith
Thekkoottuparambil Ananthanarayanan
TA
Department of Biochemistry, Amala Institute of Medical Sciences, Amala Nagar, Thrissur-680 555, Kerala, India. taajith@rediffmail.com
Anu
Vijayan
V
Riji
Thomas
T
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D000069059:Atorvastatin; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D008956:Models, Chemical; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011758:Pyrroles / Q000494:pharmacology*; D017382:Reactive Oxygen Species
D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D017382:Reactive Oxygen Species; D000069059:Atorvastatin