Autophagy inhibition improves the efficacy of curcumin/temozolomide combination therapy in glioblastomas

Abstract

Glioblastoma is a devastating primary brain tumor resistant to conventional therapies. In this study, we tested the efficacy of combining temozolomide with curcumin, a phytochemical known to inhibit glioblastoma growth, and investigated the mechanisms involved. The data showed that synergy between curcumin and temozolomide was not achieved due to redundant mechanisms that lead to activating protective autophagy both in vitro and in vivo. Autophagy preceded apoptosis, and blocking this response with autophagy inhibitors (3-methyl-adenine, ATG7 siRNA and chloroquine) rendered cells susceptible to temozolomide and curcumin alone or combinations by increasing apoptosis. While curcumin inhibited STAT3, NFκB and PI3K/Akt to affect survival, temozolomide-induced autophagy relied on the DNA damage response and repair components ATM and MSH6, as well as p38 and JNK1/2. However, the most interesting observation was that both temozolomide and curcumin required ERK1/2 to induce autophagy. Blocking this ERK1/2-mediated temozolomide and curcumin induced autophagy with resveratrol, a blood-brain barrier permeable drug, improved temozolomide/curcumin efficacy in brain-implanted tumors. Overall, the data presented demonstrate that autophagy impairs the efficacy of temozolomide/curcumin, and inhibiting this phenomenon could provide novel opportunities to improve brain tumor treatment.

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

“…42 With regard to PRKDC, its connection to the autophagy pathway is less clear, albeit there is evidence suggesting the presence of such a link. 38,43,44 The mobilization of autophagy via these DDR transducers can be prosurvival 38,39,[45][46][47][48] or antisurvival; 38,39,48,49 and the dual roles that autophagy plays in cell fate determination under DNA damage stress conditions add to the complexity of its involvement in DDR, and may influence the outcome of anticancer chemotherapy. The interplay between DDR and autophagy is a burgeoning area of research in the autophagy field, linking autophagy with genomic integrity.…”

Autophagic flux response and glioblastoma sensitivity to radiation

“…In fact, combining bafilomycin, which blocks autophagy by preventing the fusion of mature autophagosomes with lysosomes, sensitized glioma cells to temozolomide by inducing apoptotic, rather than autophagic, cell death. Zanotto-Filio et al 40 suggested that autophagy has a protective role in gliomas as temozolomide/curcumin treatment in combination with 3-methyladenine (MA) leads to a reduction in cell viability. …”

Curcumin suppresses 4-hydroxytamoxifen resistance in breast cancer cells by targeting SLUG/Hexokinase 2 pathway

“…Curcumin is a major component of the food flavour turmeric and emerges as an anticarcinogenic agent for reversing drug resistance by regulating multiple targets, including PI3K/Akt, STAT3, NF-kB, and c-Myc [3,4]. SLUG, also named as Snai2, is a zinc-finger transcription factor correlated with poor outcomes in colon, lung and ovarian cancers [5].…”