Lovastatin (LOV) enhances doxorrubicin (DOX) apoptotic and antitumoral activities in a mouse mammary adenocarcinoma (M-406) and a rat B-cell lymphoma (L-TACB)

ROZADOS V. R.; HINRICHSEN L. I.; CUELLO CARRIÓN F. D.; CIOCCA D. R.; SCHAROVSKY G. O.

Orlando, FL, USA

Congreso; 95th Annual Meeting of the American Association for Cancer Research; 2004

American Association for Cancer Research

We have previously demonstrated the in vivo antimetastatic effect of non-toxic doses of lovastatin in LTACB tumor-model. This effect would be mediated, in part, by the inhibition of p21ras membrane anchorage. Since lovastatin and doxorubicin are able to stop the cell cycle in different phases and also to induce apoptosis in several types of tumor, our aim was to study the effect of the combined treatment with LOV + DOX both in vitro and in vivo evaluating cell viability, tumor growth and apoptosis in two rodent tumor models. A cell suspension of M-406 was distributed in four groups and treated as follows: A-I) Control, with no further treatment; A-II) LOV 20 uM, A-III) DOX 8 ug/ml; A-IV) LOV 20 uM + DOX 8 ug/ml. After 24h incubation cell viability was evaluated by the MTS/PMS colorimetric assay. Cell viability of A-IV [median (range):22.3 (15-35)] was lower (P < 0.05) than that of A-I (100.0). A-II and A-III did not differ from controls but from A-IV. Inbred CBi mice were challenged s.c. with M-406 and treated as follow: B-I) Control, with no further treatment; B-II) Injected with LOV (25mg/kg) 3 times per week, from day 5 from tumor challenge; B-III) Injected with DOX (1mg/kg), twice weekly, from day 11; B-IV) Idem B-II + B-III. Tumor size on day 21 in B-IV animals was lower (P < 0.05) than in the other groups [cm3, mean ± SE; B-I: 3.08 ± 0.62 versus B-IV: 1.80 ± 0.24]. The level of apoptosis detected by TUNEL assay in B-II, B-III and B-IV tumors was higher than that observed in the control group, the highest being that corresponding to B-IV. Similar in vitro and in vivo results were obtained when a rat B cell lymphoma (L-TACB) was studied. Lovastatin, administered in non-toxic doses, increase the antitumoral effect produced by doxorubicin, an outcome that might be due, at least in part, to the enhancement of apoptosis. Thus, the combined treatment would allow the reduction of doxorubicin doses administered in vivo, diminishing the appearance of side-effects while retaining the antitumoral capacity achieved with higher doses.