Differential Effects of Lovastatin on Cisplatin Responses in Normal Human Mesothelial Cells versus Cancer Cells: Implication for Therapy

Abstract

The cancer killing efficacy of standard chemotherapeutic agents such as cisplatin (CDDP) is limited by their side effects to normal tissues. Therefore, research efforts optimizing the safety and efficacy of those agents are clinically relevant. We did screen for agents that specifically protect normal human mesothelial cells against CDDP without reducing the cancer cell killing efficacy. Lovastatin was identified from the screen. Lovastatin at a pharmacologically relevant concentration strongly arrested the proliferation of normal cells, whereas cancer cells were less affected. CDDP-induced DNA damage response was not activated and normal cells showed enhanced tolerance to CDDP when normal cells were treated with the combination of CDDP and lovastatin. We demonstrate that interfering with protein geranylgeranylation is involved in the lovastatin-mediated CDDP protective effect in normal cells. In contrast to normal cells, in cancer cells lovastatin did not change the CDDP-induced response, and cancer cells were not protected by lovastatin. Furthermore, lovastatin at the pharmacological relevant concentration per se induced DNA damage, oxidative stress and autophagy in cancer cells but not in normal mesothelial cells. Therefore, our data suggest that lovastatin has a potential to improve the therapeutic index of cisplatin-based therapy.

Lovastatin‐mediated MCF‐7 cancer cell death involves LKB1‐AMPK‐p38MAPK‐p53‐survivin signalling cascade

“…However, lovastatin-induced p21 up-regulation was likely through p53-independent pathway. 56 Lafarga et al 57 reported that p38MAPK induces p21 mRNA stabilization, resulting in p21 accumulation and cell cycle arrest. Inhibition of HDACs may also contribute to lovastatin's actions in elevating p21 in cancer cells.…”

“…survivin reduction in not only MCF-7, but also MDA-MB-231 and MDA-MB-468 cells (Figure S2). However, lovastatin-induced p21 up-regulation was likely through p53-independent pathway 56. It appears that p53-mediated survivin reduction may account for lovastatin's anti-proliferative and apoptotic effects in MCF-7 cells.…”

Anticancer properties of Monascus metabolites

“…Savas et al [46] identified ELL-associated factor 2 (EAF2), an androgen-response gene, as the mediator of LV-induced apoptosis in colorectal cancer HCT-116 cells. Furthermore, LV protected primarily cultured normal human cells but not cancer cells from cisplatin-induced cytotoxicity [41], suggesting a role for LV in protecting normal mesothelial cells from chemotherapyinduced toxicity. Furthermore, LV protected primarily cultured normal human cells but not cancer cells from cisplatin-induced cytotoxicity [41], suggesting a role for LV in protecting normal mesothelial cells from chemotherapyinduced toxicity.…”

“…Effects of lovastatin: LV, along with other statins, induced apoptosis in human lung [34], breast [35], prostate [36], colorectal [23,37], liver [38], oral [39], thyroid cancer [40], mesothelioma [41], malignant myeloma [42], and neuroblastma cells [43]. In the four lung cancer cell lines tested, A549, H460, H441, and Calu-1, LV-induced apoptosis was associated with reduction in glutathione followed by caspase-8 and caspase-3 activation [34].…”

Lovastatin prevents bleomycin-induced DNA damage to HepG2 cells

“…This method can sensitively detect the DNA damage based on micro electrophoresis (15). In this research, we used HepG2 cells (hepatoma cells) for specialized liver function and comparable activities with human hepatocytes.…”