Is Autophagy Inhibition in Combination with Temozolomide a Therapeutically Viable Strategy?

Abstract

Temozolomide is an oral alkylating agent that is used as the first line treatment for glioblastoma multiform, and in recurrent anaplastic astrocytoma, as well as having demonstrable activity in patients with metastatic melanoma. However, as the case with other chemotherapeutic agents, the development of resistance often limits the therapeutic benefit of temozolomide, particularly in the case of glioblastoma. A number of resistance mechanisms have been proposed including the development of cytoprotective autophagy. Cytoprotective autophagy is a survival mechanism that confers upon tumor cells the ability to survive in a nutrient deficient environment as well as under external stresses, such as cancer chemotherapeutic drugs and radiation, in part through the suppression of apoptotic cell death. In this review/commentary, we explore the available literature and provide an overview of the evidence for the promotion of protective autophagy in response to temozolomide, highlighting the possibility of targeting autophagy as an adjuvant therapy to potentially increase the effectiveness of temozolomide and to overcome the development of resistance.

Cytoprotective, Cytotoxic and Cytostatic Roles of Autophagy in Response to BET Inhibitors

“…Autophagy induction has been shown to be associated with various therapeutic modalities, with different functions, including cytotoxic, cytoprotective, cytostatic and non-protective forms. Importantly, and as mentioned in previous publications [3][4][5][6][7] and largely accepted in the literature, the nature of the induced autophagy is dependent on the cell line as well as the nature of the chemical compound being utilized. As summarized in Table 1, the majority of the studies showed that BET inhibitors induced autophagy in different tumor models with two main roles, cytotoxic and cytoprotective.…”

“…The cytoprotective role of autophagy has been explored extensively and multiple clinical trials have been and/or are in progress to determine whether and under which conditions the suppression of autophagy could serve to increase the effectiveness of various chemotherapeutic agents. Chloroquine (CQ) and hydroxychloroquine (HCQ) are the most widely used autophagy inhibitors in pre-clinical studies as well as in clinical trials [ 3 , 7 ]. Recently, several studies highlighting the potential modulation of dysregulated signaling pathways in autophagy have also been published [ 10 , 11 ].…”

“…JQ1 significantly suppressed the proliferation of both the U87 and GH2 cell lines. Furthermore, upon combining JQ1 with temozolomide, the standard-of-care of therapy for GBM [ 7 ], a greater anti-proliferative response was evident compared to each drug alone, together with increased apoptosis. JQ1 treatment also promoted marked morphological changes in both cell lines, such as increasing the number of GBM cells with cytoplasmic extensions and elongation, suggesting the induction of a differentiation process.…”

“…This manuscript is one of a series of papers that highlight the different roles of autophagy in response to various cancer therapeutic modalities. Our previous publications assessed the influence of autophagy in tumor cells on the response/sensitivity to radiation [ 1 ], cisplatin [ 2 ], microtubule poisons [ 3 ], hormonal therapies in estrogen-positive breast cancer [ 4 ], PARP inhibitors [ 5 ], Topoisomerase I poisons [ 6 ] and, most recently, temozolomide [ 7 ]. Our overarching goal is to determine whether there are particular therapeutic modalities where the preclinical data, and, where available, clinical trials, support the inclusion of autophagy inhibition as an adjuvant approach.…”

Regorafenib and glioblastoma: a literature review of preclinical studies, molecular mechanisms and clinical effectiveness

“… 34 ). Autophagy has been reported in GBM in response to TMZ, and it has been hypothesised that it confers a compromised therapeutic response (Refs 35 , 36 ). Regorafenib-dependent autophagy in GBM, as reported in (Ref.…”