Abstract
Corosolic acid is one of the pentacyclic triterpenoids isolated from Lagerstroemia speciose and has been reported to exhibit anti-cancer and anti-proliferative activities in various cancer cells. In the present study, we investigated the molecular mechanisms of corosolic acid in cancer cell death. Corosolic acid induces a decrease of cell viability and an increase of cell cytotoxicity in human renal carcinoma Caki cells. Corosolic acid-induced cell death is not inhibited by apoptosis inhibitor (z-VAD-fmk, a pan-caspase inhibitor), necroptosis inhibitor (necrostatin-1), or ferroptosis inhibitors (ferrostatin-1 and deferoxamine (DFO)). Furthermore, corosolic acid significantly induces reactive oxygen species (ROS) levels, but antioxidants (N-acetyl-l-cysteine (NAC) and trolox) do not inhibit corosolic acid-induced cell death. Interestingly, corosolic acid induces lipid oxidation, and α-tocopherol markedly prevents corosolic acid-induced lipid peroxidation and cell death. Anti-chemotherapeutic effects of α-tocopherol are dependent on inhibition of lipid oxidation rather than inhibition of ROS production. In addition, corosolic acid induces non-apoptotic cell death in other renal cancer (ACHN and A498), breast cancer (MDA-MB231), and hepatocellular carcinoma (SK-Hep1 and Huh7) cells, and α-tocopherol markedly inhibits corosolic acid-induced cell death. Therefore, our results suggest that corosolic acid induces non-apoptotic cell death in cancer cells through the increase of lipid peroxidation.
Highlights
Reactive oxygen species (ROS) are formed as a byproduct of the metabolism of oxygen and have critical roles in cell homeostasis and signaling [1]
We investigated whether corosolic acid induces cell death, and identified the molecular mechanism of corosolic acid-induced cell death in human renal carcinoma Caki cells
Because corosolic acid has an anti-cancer effect in various cancer cells [11,12,13,15,16,18], we examined whether corosolic acid induces cell death in renal carcinoma Caki cells
Summary
Reactive oxygen species (ROS) are formed as a byproduct of the metabolism of oxygen and have critical roles in cell homeostasis and signaling [1]. Lipid peroxidation induces oxidative degradation of lipids, eventually resulting in damage of cancer cells [5]. It is involved in the underlying mechanisms of several diseases, such as cancer, senescence, and neurodegenerative diseases [6,7]. Corosolic acid has been investigated for its anti-diabetic activity in animal models through development of glucose metabolism [10]. It has been reported for anti-tumor and anti-proliferative activities against many human cancer cells. The anti-cancer activity of corosolic acid in human renal carcinoma cells has not yet been investigated. We investigated whether corosolic acid induces cell death, and identified the molecular mechanism of corosolic acid-induced cell death in human renal carcinoma Caki cells
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