Abstract
Glioblastoma (GBM) is one of the most aggressive malignant tumors with an overall dismal survival averaging one year despite multimodality therapeutic interventions including surgery, radiotherapy and concomitant and adjuvant chemotherapy. Few drugs are FDA approved for GBM, and the addition of temozolomide (TMZ) to standard therapy increases the median survival by only 2.5 months. Targeted therapy appeared promising in in vitro monolayer cultures, but disappointed in preclinical and clinical trials, partly due to the poor penetration of drugs through the blood brain barrier (BBB). Cancer stem cells (CSCs) have intrinsic resistance to initial chemoradiation therapy (CRT) and acquire further resistance via deregulation of many signaling pathways. Due to the failure of classical chemotherapies and targeted drugs, research efforts focusing on the use of less toxic agents have increased. Interestingly, multiple natural compounds have shown antitumor and apoptotic effects in TMZ resistant and p53 mutant GBM cell lines and also displayed synergistic effects with TMZ. In this review, we have summarized the current literature on natural products or product analogs used to modulate the BBB permeability, induce cell death, eradicate CSCs and sensitize GBM to CRT.
Highlights
Tumors of the central nervous system (CNS) represent 1.4% of all newly diagnosed cancers and 2.6% of cancer deaths in 2015 [1]
We have summarized the current literature on natural products or product analogs used to modulate the blood brain barrier (BBB) permeability, induce cell death, eradicate Cancer stem cells (CSCs) and sensitize GBM to chemoradiation therapy (CRT)
The efficacy of TMZ, a DNA alkylating agent used in first line therapy, is weakened by the expression of methylguanine-DNA methyl transferase (MGMT), which repairs the DNA damage induced by TMZ
Summary
Tumors of the central nervous system (CNS) represent 1.4% of all newly diagnosed cancers and 2.6% of cancer deaths in 2015 [1]. Another study showed that resveratrol increased TMZ toxicity by increasing reactive oxygen species (ROS) generation, AMPK pathway activation, mTOR signaling inhibition and decreased antiapoptic protein Bcl-2 expression in SHG44 GBM cells [33].
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