Lovastatin potentiates antitumor activity of doxorubicin in murine melanoma via an apoptosis‐dependent mechanism

Abstract

Lovastatin, a drug successfully used in the clinic to prevent and to treat coronary heart disease, has recently been reported to decrease the incidence of melanoma in lovastatintreated patients. Lovastatin has also been proved to potentiate antitumor effects of both cisplatin and TNF-␣ in murine melanoma models. Recently, an augmented therapeutic effect of lovastatin and doxorubicin has been reported in 3 tumor models in mice. In our preliminary study lovastatin caused retardation of melanoma growth in mice treated with doxorubicin (Feleszko et al. J Natl Cancer Inst 1998;90:247-8). In the present report, we supplement our preliminary observations and demonstrate in 2 murine and 2 human melanoma cell lines that lovastatin effectively potentiates the cytostatic/cytotoxic activity of doxorubicin in vitro via an augmentation of apoptosis (estimated with PARP-cleavage assay, annexin V assay and TUNEL) . The combined antiproliferative activity of lovastatin and doxorubicin was evaluated using the combination index (CI) method of Chou and Talalay, revealing synergistic interactions in melanoma cells exposed to lovastatin and doxorubicin. In B16F10 murine melanoma model in vivo, we have demonstrated significantly increased sensitivity to the combined treatment with both lovastatin (5 mg/kg for 14 days) and doxorubicin (4 ؋ 1 mg/kg) as compared with either agent acting alone. Lovastatin treatment resulted also in significant reduction of the number of experimental metastasis in doxorubicin-treated mice. The results of our studies suggest that lovastatin may enhance the effectiveness of chemotherapeutic agents in the treatment of malignant melanomas.

Lipid‐lowering agents and risk of melanoma

“…A synergic effect with other antineoplastic agents, including doxorrubicine and selective cyclooxygenase inhibitors, has been observed. 5,6 While our small sample size limited the statistical power, we found a similar trend for improvement in melanoma risk. Further evaluation of the anticancer effects for statin drugs with a larger sample is warranted.…”

Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells

“…At the present time, no association studies involving fluvastatin have been published yet; however, it has been previously shown that lovastatin enhanced the apoptosis induced by chemotherapeutic drugs, including 5-FU and cisplatin, in colon cancer cell lines (Agarwal et al, 1999). Furthermore, Holstein and Hohl (2001b) demonstrated synergism between paclitaxel and lovastatin on human cancer cell lines, whereas Feleszko et al (2002) showed an in vivo enhanced antitumour activity of doxorubicin in murine tumour models when associated with lovastatin.…”

The HMG-CoA reductase inhibitor simvastatin overcomes cell adhesion–mediated drug resistance in multiple myeloma by geranylgeranylation of Rho protein and activation of Rho kinase

“…26 Mevastatin, for example, inhibits bone resorption and induces osteoclast apoptosis in vitro by inhibition of protein prenylation. 27 Furthermore, statins have been shown to induce apoptosis in melanoma, 28 thyroid cancer, [29][30] colon carcinoma, 32,33 squamous cell carcinoma, 34 breast cancer, 35 acute myeloid leukemia, 36 malignant lymphoma, 37 and multiple myeloma cells 14,38 in vitro. In our experiments, statins have been used in much lower concentrations than in most in vitro studies published with complete reversal of CAM-DR, suggesting realistically achievable doses in humans.…”