Cholesterol-Lowering Phytochemicals: Targeting the Mevalonate Pathway for Anticancer Interventions.

There are a plethora of cancer causes and the road to fully understanding the carcinogenesis process remains a dream that keeps changing. However, a list of role players that are implicated in the carcinogens process is getting lengthier. Cholesterol is known as bad sterol that is heavily linked with cardiovascular diseases; however, it is also comprehensively associated with carcinogenesis. There is an extensive list of strategies that have been used to lower cholesterol; nevertheless, the need to find better and effective strategies remains vastly important. The role played by cholesterol in the induction of the carcinogenesis process has attracted huge interest in recent years. Phytochemicals can be dubbed as magic tramp cards that humans could exploit for lowering cancer-causing cholesterol. Additionally, the mechanisms that are regulated by phytochemicals can be targeted for anticancer drug development. One of the key role players in cancer development and suppression, Tumour Protein 53 (TP53), is crucial in regulating the biogenesis of cholesterol and is targeted by several phytochemicals. This minireview covers the role of p53 in the mevalonate pathway and how bioactive phytochemicals target the mevalonate pathway and promote p53-dependent anticancer activities.

Downregulation of RBBP6 variant 1 during arsenic trioxide-mediated cell cycle arrest and curcumin-induced apoptosis in MCF-7 breast cancer cells.

AIM: To determine the expression patterns of the RBBP6 spliced variants during arsenic trioxide-mediated cell cycle arrest and curcumin-induced apoptosis in MCF-7 cells. MATERIALS & METHODS: As2O3 and curcumin were used to study cytotoxicity, cell cycle arrest, apoptosis and the expression of RBBP6 variants. The MUSE Cell Analyser was used to analyze cell cycle arrest, apoptosis and multicaspase activity while apoptosis was further confirmed using microscopy. Semi-quantitative RT-PCR was employed to quantitate the expression of the RBBP6 variants. RESULTS: This study showed that the MCF-7 cells expressed RBBP6 variant 1 but lacked both variant 2 and variant 3. Both As2O3 and curcumin significantly downregulated RBBP6 variant 1 (p < 0.001). CONCLUSION: RBBP6 variants are promising therapeutic targets.

Survivin Splice Variants in Arsenic Trioxide (As2O3)-Induced Deactivation of PI3K and MAPK Cell Signalling Pathways in MCF-7 Cells.

Several pathways are deregulated during carcinogenesis but most notably, tumour cells can lose cell cycle control and acquire resistance to apoptosis by expressing a number of anti-apoptotic proteins such as the Inhibitors of Apoptosis Protein (IAP) family of proteins that include survivin, which is implicated in cancer development. There is no study which had proven that arsenic trioxide (As2O3) has any effect on the splicing machinery of survivin and its splice variants, hence this study was aimed at determining the cytotoxic effect of As2O3 and its effect on the expression pattern of survivin splice variants in MCF-7 cells. As2O3 inhibited the growth of the MCF-7 cells in a concentration-dependent manner. The Muse® Cell Analyser showed that As2O3-induced G2/M cell cycle arrest, promoted caspase-dependent apoptosis without causing any damage to the mitochondrial membrane of MCF-7 cells. As2O3 also deactivated two survival pathways, Mitogen-Activated Protein Kinase (MAPK) and Phosphoinositide 3-Kinase (PI3K) signalling pathways in MCF-7 cells. Deactivation of the two pathways was accompanied by the upregulation of survivin 3α during As2O3-induced G2/M cell cycle arrest and apoptosis. Survivin 2B was found to be upregulated only during As2O3-induced G2/M cell cycle arrest but downregulated during As2O3-induced apoptosis. Survivin wild-type was highly expressed in the untreated MCF-7 cells, the expression was upregulated during As2O3-induced G2/M cell cycle arrest and it was downregulated during As2O3-induced apoptosis. Survivin variant ΔEx3 was undetected in both untreated and treated MCF-7 cells. Survivin proteins were localised in both the nucleus and cytoplasm in MCF-7 cells and highly upregulated during the As2O3-induced G2/M cell cycle arrest, which can be attributed to the upregulation of survivin-2B. This study has provided the first evidence showing that the novel survivin 2B splice variant may be involved in the regulation of As2O3-induced G2/M cell cycle arrest only. This splice variant can therefore, be targeted for therapeutic purposes against Luminal A breast cancer cells.