Antitumor effects of the combination of cholesterol reducing drugs

Abstract

Abstract. there are a number of potential mechanisms linking cholesterol homeostasis to processes that are tightly linked with carcinogenesis. statins, which are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMg-coAr), the rate-limiting enzyme in the mevalonic acid synthesis pathway, exert cytostatic and cytotoxic effects towards tumor cells. It seems that the cytostatic and cytotoxic effects of statins result from blocking protein prenylation, leading to inhibition of isoprenoid compound synthesis. Another compound which affects cholesterol metabolism is the plant alkaloid berberine. the aim of this study was to investigate potential antitumor effects of lovastatin combined with berberine. combined with berberine, lovastatin appeared to exert potentiated cytostatic and/or cytotoxic effects against human MDA-MB231 breast cancer and murine panc 02 pancreatic cancer cells. the obtained results indicated that the effect of berberine is not dependent on blocking protein prenylation in cells, and the toxic effect of lovastatin combined with berberine is reversed by addition of the substrates of this pathway to the level brought out by lovastatin alone. lovastatin-berberine combination caused cell cycle inhibition in g1 phase after 48 h of incubation with drugs. In a panc 02 pancreatic cancer model in mice, lovastatin-berberine combination slightly, but significantly, slowed down tumor growth. taking into account the number of patients treated with the investigated drugs one may suppose that the described interactions may be of clinical value. Introductioncholesterol-reducing agents continuously attract enormous interest not only because of their beneficial cardiovascular effects, but also due to their influence on numerous physiological and pathophysiological processes (1-3). For example, statins, which are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMg-coA) reductase target mevalonate pathway of cholesterol synthesis and impair production of isoprenoid compounds such as dolichol, ubiquinone and mevalonate-derived prenyl groups that are attached post-translationally to approximately 1% of all cellular proteins (4,5). By affecting cellular cholesterol synthesis statins also influence the formation of lipid rafts which are water insoluble plasma membrane microdomains enriched in receptors and signal transduction molecules (6). the interference with so many critical biochemical processes makes their effects extremely pleiotropic. Although statins have so far been approved only for prophylaxis or treatment of cardiovascular diseases they also show some promising therapeutic activity in the management of Alzheimer's disease, osteoporosis, graft rejection and cancer (7,8).Despite alarming results of carcinogenicity studies in rodents (9-11) clinical observations did not show an overall increase in cancer incidence or mortality among statin users (12)(13)(14). In fact statins were rather associated with reductions in the incidence of colorectal, prostate and lung cancers as well as in melanoma (15...

Berberine alleviates ox-LDL induced inflammatory factors by up-regulation of autophagy via AMPK/mTOR signaling pathway

“…AMPK is required for the protective effects of berberine in cardiovascular diseases [ 37 ]. Berberine significantly increased AMPK activity via reactive oxygen species (ROS) production and knockdown of AMPKα1 abolished the effect of berberine [ 38 ]. The mammalian target of rapamycin (mTOR) kinase is a central inhibitor of autophagy.…”

Combined Cancer Therapy with Non-Conventional Drugs: All Roads Lead to AMPK

“…Most importantly, berberine strongly increased AMPK activity via reactive oxygen species (ROS) production and inhibited tumor cell adhesion and invasion. Furthermore, knockdown of AMPKα1 abolished the effect of berberine [63].…”

Effects of Berberine against Pancreatitis and Pancreatic Cancer

“…Lovastatin is a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor that blocks cholesterol synthesis and is predominately used to treat cardiovascular disease. Panc02 cells were treated with increasing concentrations of BBR (0–5 µM) or lovastatin (0–0.12 µM) for 48 h, alone and in combination, and cell viability was assessed with crystal violet staining [ 109 ]. Both drugs showed dose-dependent inhibition of cell viability and the combination of both drugs had highly synergistic cytostatic/cytotoxic effects.…”