Proapoptotic and antitumor activities of the HMG-CoA reductase inhibitor, lovastatin, against Dalton's lymphoma ascites tumor in mice.
BACKGROUND
Diet rich in fat have a clear effect on the tumor incidence in humans. Increased level of lipid peroxidation were found in colon, liver, breast and kidney carcinogenesis. Although the beneficial effects of statins for cardiovascular diseases are well established, their importance in the area of cancer therapeutics has recently gained recognition. Many studies of lovastatin in in vitro systems and experimental animals have been reported as an effective antitumor agent. However, phase I/II clinical trials in cancer patients demonstrated a minor to non-significant responses. Hence more studies in different tumor models using doses corresponding to that used to reduce lipid in human are required to support the antitumor activity.


METHODS
The antitumor activity was evaluated using Daltons' Lymphoma Ascites (DLA) cell line-induced ascites tumor model in mice. Proapoptotic activity was evaluated in DLA cell line induced ascites animals after the treatment of lovastatin. Apoptosis was analyzed morphologically by staining with Giemsa and biochemically by observing the laddering of DNA in agarose gel electrophoresis. In vitro cytotoxic activity of lovastatin was studied by trypan blue dye exclusion method. Lipid peroxidation inhibiting activity was demonstrated in Fe2+-ascorbate induced rat whole liver homogenate.


RESULTS
Lovastatin dose dependently inhibited the ascites tumor growth at 4 and 16 mg/kg body wt (p.o). The percentage increase in life span (%ILS) in the 16 mg/kg treated group was 61.8% (P<0.01). Single dose of lovastatin (16 mg/kg body wt, p.o) was also effective to accelerate the apoptosis in the ascites tumor bearing mice that was evident from the multiple fragmentation of DNA in gel electrophoresis. Further the morphological analysis of DLA cells aspirated from the lovastatin treated animals showed a significant (P<0.01) increase of apoptotic cells (15.5+/-3%) than the control animals (6.5+/-1%). Concentration of lovastatin required for the 50% of the cytotoxicity was 37+/-5 microg/ml. Lovastatin at its low concentrations were effective to inhibit lipid peroxidation.


CONCLUSIONS
The antitumor activity of lovastatin against the ascites tumor is due to its proapoptotic and cytotoxic activities. Lovastatin at low concentrations inhibited Fe2+ induced lipid peroxidation in in vitro system. The proapoptotic and lipid peroxidation inhibiting activities of the lipid lowering drug lovastatin may further suggest its possible therapeutic use as a cancer chemopreventive agent.
Ajith
T A
TA
Department of Biochemistry, Amala Institute of Medical Sciences, Amala Nagar, Thrissur, Kerala 680 555, India. taajith@rediffmail.com
Harikumar
K B
KB
Thasna
H
H
Sabu
M C
MC
Babitha
N V
NV
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015227:Lipid Peroxidation / Q000187:drug effects; D008148:Lovastatin / Q000494:pharmacology* / Q000627:therapeutic use; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D016019:Survival Analysis
D000970:Antineoplastic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin