Inhibiting the expression of BCL-2 protein using BH3-mimetic drugs can disrupt the intrinsic apoptotic pathway in MPM (malignant pleural mesothelioma) cell lines. Thus significantly enhancing the apoptosis (cell death) of tumor cells, and improving the survival time.
Scientists from the Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia have shared a potential target "worthy of consideration for future clinical investigation" for treating malignant pleural mesothelioma by studying the defects in the apoptotic intrinsic signaling pathway.
Defective Intrinsic Apoptotic Signaling Pathway- Major Hallmark of Cancer
Apoptosis simply means "programmed cell death" that can be intrinsic or extrinsic, based on the sources. Intrinsic apoptosis occurs with internal stimuli and it originates from within the target cell whereas extrinsic with external stimuli.
The intrinsic apoptotic pathway is mainly facilitated by the BCL-2 proteins family. In some human cancers, the BCL-2 protein-coding gene was highly expressed. This means that some members of the BCL-2 family promote cell death (pro-apoptotic) and some inhibit cell death (anti-apoptotic).
Enhanced expression of anti-apoptotic proteins is a major defect in the intrinsic apoptotic pathway which leads to cancer.
Though, the significance of the intrinsic apoptosis pathway in MPM patients is not thoroughly studied yet. However, BCL-XL is reported to be a commonly over-expressed anti-apoptotic BCL-2 family protein in major MPM subtypes' cell lines. And in comparison to other tumors, in MPM subtypes, BCL-XL expression is particularly higher.
BCL-XL often exists along with MCL-1 proteins, showing its co-dependence on MCL-1.
Inhibition of BCL-XL Impressively Reduce MPM Tumor
Decreasing the expression of BCL-XL can enhance apoptosis of the MPM tumor cells. In this regard, much work has been done in recent years and researchers have found the solution in the form of BH3-mimetics.
BH3-mimetics are small molecules that act as BCL-2 inhibitors. For example, ABT-737 or its bioavailable analog ABT-263/“Navitoclax”, directly targets anti-apoptotic members of the BCL-2 family, namely BCL-2, BCL-XL, and BCL-W.
Potential Treatment Options
In this study, Australian scientists particularly studied the effects of BH3-mimetics on both BCL-XL and MCL-1; along with testing combined effects of cisplatin and BCL-XL inhibitors. The results were quite promising.
"Data demonstrate that for maximal cell killing with BCL-XL inhibition in MPM, MCL-1 must also be antagonized".
Another way of increasing tumor cell death is through shared targeting of BCL-2 family proteins by BH3-mimetics.
Combining standard-of-care treatment with Cisplatin along with A-1331852, a BCL-XL inhibitor resulted in remarkably increased tumor cell death/ apoptosis and decreased tumor proliferation.
The lead author, Surein Arulananda wrote,
"Our studies are the first to demonstrate that MCL-1 and BCL-XL co-targeting with BH3-mimetics synergistically increases MPM cell killing in all MPM subtypes."
Clinical trials based on the information gathered through this research can provide a potential treatment method for MPM subtypes. To find out more about the current clinical advancements in mesothelioma treatment options, visit here.