α-Mangostin Enhances Betulinic Acid Cytotoxicity and Inhibits Cisplatin Cytotoxicity on HCT 116 Colorectal Carcinoma Cells

Abstract

Despite the progress in colon cancer treatment, relapse is still a major obstacle. Hence, new drugs or drug combinations are required in the battle against colon cancer. α-Mangostin and betulinic acid (BA) are cytotoxic compounds that work by inducing the mitochondrial apoptosis pathway, and cisplatin is one of the most potent broad spectrum anti-tumor agents. This study aims to investigate the enhancement of BA cytotoxicity by α-mangostin, and the cytoprotection effect of α-mangostin and BA on cisplatin-induced cytotoxicity on HCT 116 human colorectal carcinoma cells. Cytotoxicity was investigated by the XTT cell proliferation test, and the apoptotic effects were investigated on early and late markers including caspases-3/7, mitochondrial membrane potential, cytoplasmic shrinkage, and chromatin condensation. The effect of α-mangostin on four signalling pathways was also investigated by the luciferase assay. α-Mangostin and BA were more cytotoxic to the colon cancer cells than to the normal colonic cells, and both compounds showed a cytoprotective effect against cisplatin-induced cytotoxicity. On the other hand, α-mangostin enhanced the cytotoxic and apoptotic effects of BA. Combination therapy hits multiple targets, which may improve the overall response to the treatment, and may reduce the likelihood of developing drug resistance by the tumor cells. Therefore, α-mangostin and BA may provide a novel combination for the treatment of colorectal carcinoma. The cytoprotective effect of the compounds against cisplatin-induced cytotoxicity may find OPEN ACCESSMolecules 2012, 17 2940 applications as chemopreventive agents against carcinogens, irradiation and oxidative stress, or to neutralize cisplatin side effects.

Synergic Effect ofα-Mangostin on the Cytotoxicity of Cisplatin in a Cervical Cancer Model

“…α -M has also been associated with cell cycle arrest in the G2M phase by regulating expression of cdc2 cyclin and p27 [44]. Recently, Aisha and coworkers [45] found that α -M induces apoptosis by several mechanisms, such as through the Myc/Max and MAPK/ERK signaling pathways and the downregulation of the NFkB pathway. In this study, we designed two experimental schemes to study several mechanisms for both drugs.…”

“…However, when α -M was coincubated with CDDP, the percentage of cell viability did not decrease more than 60 percent (Figure 1(a)), indicating that low concentrations of α -M protect the cells against CDDP damage. In this sense, Aisha and coworkers [45] reported that at low concentrations, α -M significantly reduced CDDP cytotoxicity on colorectal carcinoma cells. However, when the cells were exposed first to α -M and then CDDP, the response was contrary.…”

Betulinic Acid: Recent Advances in Chemical Modifications, Effective Delivery, and Molecular Mechanisms of a Promising Anticancer Therapy

“…The antiproliferative and apoptosis‐inducing mechanisms of BetA explain its mode of action. Biological activity of BetA was first demonstrated in melanoma cell lines and later in breast , brain tumor , prostate , colon, leukemia , head and neck , and cervical tissues (Table ). Activity has been shown in primary tumor samples and later confirmed in melanoma xenograft mouse models .…”

Antioxidative vs cytotoxic activities of organotin complexes bearing 2,6‐di‐tert‐butylphenol moieties

“…For comparison of cytotoxicity and establishment of the leader compound the organotin complexes 3 , 4 , 6 , 7 based on 2,6‐di‐ tert ‐butyl‐4‐mercaptophenol were also tested against 8 types of human cancer cell lines. The activity was compared with literature data for cisplatin …”