Lovastatin inhibits tumor growth and lung metastasis in mouse mammary carcinoma model: a p53-independent mitochondrial-mediated apoptotic mechanism

Abstract

The effects of lovastatin, a potent inhibitor of hydroxymethylglutaryl-coenzyme A reductase, were studied in a mouse model of metastatic mammary cancer carrying a p53 mutation. Mice bearing mammary tumors, induced by inoculation of syngeneic BALB/c mice with BJMC3879 cells, were treated with lovastatin at 0, 25 and 50 mg/kg three times a week. Tumor volumes were significantly reduced in a dose-dependent manner throughout the 6 week study and were associated with both a decrease in DNA synthesis and an increase in apoptosis. The high dose of lovastatin also inhibited lung metastasis. In a corollary in vitro study, flow cytometric analyses of lovastatin-treated mammary cancer cells additionally showed cell cycle arrest at G1 phase and decreases in S and G2/M phases. Laser scanning cytometric analyses further demonstrated that cancer cells in S and G2/M were particularly susceptible to the effects of lovastatin. Transmission electron microscopic evaluation of TUNEL-confirmed apoptotic bodies in lovastatin-treated mammary carcinoma cells revealed many free 3'-OH ends of DNA in condensed chromatin within fragmented nuclei that occasionally assumed a characteristic half-moon shape. Consistent with initiation of apoptosis, cellular caspase-8, caspase-9 and caspase-3 activities were elevated in lovastatin-treated cells. The mitochondrial membrane potential was also decreased, with subsequent release of cytochrome c. However, lovastatin-induced cell death was significantly reduced by the broad spectrum caspase inhibitor z-VAD-fmk, as well as the caspase-9 inhibitor z-LEHD-fmk and the caspase-3 inhibitor z-DEVD-fmk, but not by the specific caspase-8 inhibitor z-IETD-fmk. Since immunoelectron microscopy showed translocation of Bax to the mitochondria in lovastatin-treated cells, lovastatin-induced apoptosis may, therefore, be ultimately dependent on Bax induction of cytochrome c release. These results suggest that lovastatin may be useful as an adjuvant therapy in breast cancers containing p53 mutations due to its ability to both suppress DNA synthesis and induce p53-independent mitochondria-mediated apoptosis.

Synergistic Cytotoxic Effect of Statins and Bisphosphonates on Squamous Cell Carcinoma Cell Line

“…In addition to their effects on the proliferative pathways, it is important to note that Statins are currently under intense research regarding their role in immunomodulation, proteasome inhibition and disruption of pathways associated with inflammation and angiogenesis validating their anti-neoplastic properties [32][33][34][35][36][37][38][39][40].…”

Electrogene therapy using endostatin, with or without suicide gene therapy, suppresses murine mammary tumor growth and metastasis

“…25 The BJMC3879 mammary adenocarcinoma cell line was subsequently derived from a metastatic focus within a lymph node from one of the inoculated mice and the cell line continues to show a high metastatic propensity, especially to lymph nodes and lungs. 13,24,26 We maintain the BJMC3879 line in Roswell Park Memorial Institute-1640 medium containing 10% fetal bovine serum supplemented with streptomycin/penicillin in an incubator under a 5% CO 2 atmosphere.…”

Suppression of cell proliferation, induction of apoptosis and cell cycle arrest: Chemopreventive activity of vanadium in vivo and in vitro

“…[28][29][30][31][32][33] Recent evidence shows that suppression of apoptosis by tumor promoting agents in preneoplastic cells is an important mechanism in tumor promotion. 34 Again, the tumor suppressor gene p53 is required for checkpoint control during cell cycle progression, as well as induction of apoptosis. 35 The overexpression of p53 inhibits cell proliferation.…”