Glioblastoma multiforme, a common highly malignant brain tumor is composed of invasive proliferating cancer cells, and a small population of glioblastoma stem cells characterized by relative quiescence, self-renewal, pluripotency, resistance to conventional chemotherapy, immunotherapy, and radiation. These glioblastoma stem cells if not eradicated following current standard of care, lead to tumor recurrence. By expressing a spectrum of phenotypic markers, associated competencies and a variety of growth patterns, tumor recurrence accounts for a lack of survival benefit . To remedy this recurrence issue, it is necessary to eliminate glioblastoma stem cells subsets. This will require a significant change in current therapeutic approach i.e. the application of Withaferin A or a combination of pleiotropic agents as suggested in a previous publication.
Keywords: Tumor Stem Cells; Glioblastoma Multiforme; Withaferin A; Pleiotropic Agents
Glioblastoma multiforme is characterized by tumor cell heterogeneity, and by recurrent invasive tumors following conventional radiation, cytotoxic drugs, and limited ablative surgery [1-5]. The tumor originates from a stem cell population which exhibits properties of self-renewal and multi-lineage differentiation followed by clonal evolution, hierarchical stem cell development and bidirectional inter-conversion with nonstem cells . These observations indicate that it is necessary to eradicate glioblastoma stem cells in order to abrogate the enhanced risk of tumor recurrence following conventional chemotherapy surgery, and radiation. The therapeutic focus should initially consist of applying pleiotropic medicinal (supplements, drugs) directed to the multiple molecular pathways promoting tumor stem cell genesis. Based on published pre-clinical research , pleiotropic compounds such as withaferin A,  and curcumin can be considered appropriate candidate agents . There are several published withaferin A inhibitory interactions with critical molecular pathways in glioblastoma stem cells promoting tumor development (Table 1), There are also pre-clinical studies with withaferin A prohibiting tumor development in other tumors, but unexplored in glioblastoma stem cells (Tables 2 & 3).
Gliomagenesis and tumor stem cell heterogeneity are promoted by genetic alterations(driver mutations) and multiple factors in the surrounding tumor microenvironment [47,48] An additional mechanism for post-therapeutic reestablishment of an invasive and chemo/ radiation resistance population of differentiated glioblastoma cancer cells into cancer stem-like cells expressing markers associated with pluripotency and stemness such as CD133, SOX2, Oct4, and Nestin has been published . These observations emphasize the importance of preclinical research studies with pleiotropic compounds interacting in a specific manner with tumor stem cells and avoiding interacting with normal stem cells. In the clinical setting, Withaferin A alone, or in combination with other pleiotropic approved drugs or supplements as initial therapy following diagnosis of glioblastoma multiforme [49-53] may prohibit or delay tumor recurrence assuming these agents abrogate the effects of driver mutations, and micro-environmental factors.
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