Apoptotic induction by simvastatin in human lung cancer A549 cells via Akt signaling dependent down-regulation of survivin

Abstract

Statins, HMG-CoA reductase inhibitors have been studied for their antiproliferative and proapototic effects. Recently, statin-induced apoptosis has been associated with down-regulation of survivin expression in cancer cells. However, the mechanism of deregulated survivin by simvastatin on lung cancer is still unclear. Herein, we demonstrated that simvastatin induced caspase-dependent apoptosis in A549 lung cancer cells. Simvastatin also resulted in a decrease in the expression of phosphorylated Akt. In addition, simvastatin effectively down-regulated survivin mRNA and protein, but not cIAP-1 and cIAP-2. The combination of simvastatin and 10 μM LY294002 (non-toxic dose) augmented apoptosis significantly, as evidenced by cleavage of PARP. The immunoreactive band of survivin was markedly decreased in cells treated with 50 μM LY294002 (toxic dose) as well as by the combination of simvastatin and 10 μM LY294002. Moreover, survivin down-regulation by RNA interference induced apoptosis accompanied by an increase in hypodiploid DNA content. Taken together, these data suggest that the anti-cancer effect of simvastatin via induction of apoptosis is related to Akt signaling dependent down-regulation of survivin in lung cancer A549 cells.

The pleiotropic effects and therapeutic potential of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in malignancies: A comprehensive review

“…Benefi cial effects Adverse effects Breast cancer [12][13][14][15] 18% reduction in incidence with hydrophobic statin use (P = 0.02) Use of hydrophobic statins associated with a fourfold increased risk of progesterone receptor-negative breast cancer 37% reduction in estrogen receptor/progesterone receptornegative cancer (P = 0.02) Low-grade and less-invasive tumor burden 33% decreased cancer recurrence after conventional treatment (P = 0.02) Colon cancer [16][17][18][19][20][21][22][23][24] Approximately 10% reduction in the risk of colorectal carcinoma 39% increased risk of newly detected adenomas in patients taking statins for at least 3 years (P = 0.024) 49% reduction in adenomatous polyp recurrence 3-5 years post initial polypectomy (P < 0.01) 54% increased risk of new colorectal adenomas in type two diabetics prescribed statins for 3 years who had a prior history of colorectal adenomas (P = 0.007) Smaller number of polyps (P = 0.002) and polyp size (P = 0.03) Lower incidence of advanced polyps (P = 0.03) Synergestic effects with conventional chemotherapeutic agents Prostate cancer [25][26][27][28][61][62][63] 8% reduced risk of prostate cancer 55% increased risk in total prostate cancer with everuse of statins in men aged 50 years or older Signifi cant reduction in high-grade or high-volume disease Improved freedom from biochemical failure (P < 0.001) and salvage therapy (P = 0.001) Improved relapse-free survival (P < 0.001) 69% reduction in intratumoral infl ammation (P = 0.047) Hepatocellular cancer [29][30][31] 8-month (P = 0.003) to 9-month (P = 0.006) longer survival when statin added to transarterial embolization therapy ± chemotherapy 37% reduction in hepatocellular cancer among diabetics Hematologic cancers [32-35, 86,87] 39% decreased incidence of lymphomas Increased osteoclast activity in multiple myeloma patients treated with statins 55% improved event-free survival in follicular lymphoma (P = 0.001) Greater than two-fold increase in statin use among patients with lymphoma or multiple myeloma compared with patients with orthopedic (P = 0.009) or otorhinolaryngolic (P = 0.001) malignancies 60% decreased risk of multiple myeloma Reduced resistance drug-refractory multiple myeloma Miscellaneous [36]…”

“…Additionally, statins may sensitize lung cancer cells to the effects of chemotherapy and ionizing radiation by impairing various growth factors and inducing the apoptosis of cancer cells via the inhibition of the Akt pathway, which plays a major role in tumor cell proliferation, survival and invasiveness. [65][66]28] Other in vitro studies have shown that statins modulate the activity of tumor suppressors, proinflammatory proteases and cell cycle regulatory proteins, inhibiting the formation of lung cancer cells. [67][68][69] Clinical data regarding the use of statins as anti-tumor or therapeutic agents in lung cancer is limited.…”

Triticumoside induces apoptosis via caspase-dependent mitochondrial pathway and inhibits migration through downregulation of MMP2/9 in human lung cancer cells

“…However, the results showed that they are not effective. Thus, effective diagnosis and identification of effective molecular therapeutic agents are required to treat lung cancer [2].…”

Simvastatin-induced up-regulation of gap junctions composed of connexin 43 sensitize Leydig tumor cells to etoposide: An involvement of PKC pathway

“…The concentrations of simvastatin used in the present study was lower and the exposure time is particularly much shorter compared with that used in most of in vitro cancer cells (Campbell et al, 2006;Hwang et al, 2010). Up to 25 M, simvastatin did not produce any toxic effect on MLTC-1 cells (Data not shown).…”