Curcumin in Combination with Other Adjunct Therapies for Brain Tumor Treatment: Existing Knowledge and Blueprint for Future Research

Abstract

Malignant brain tumors proliferate aggressively and have a debilitating outcome. Surgery followed by chemo-radiotherapy has been the standard procedure of care since 2005 but issues of therapeutic toxicity and relapse still remain unaddressed. Repurposing of drugs to develop novel combinations that can augment existing treatment regimens for brain tumors is the need of the hour. Herein, we discuss studies documenting the use of curcumin as an adjuvant to conventional and alternative therapies for brain tumors. Comprehensive analysis of data suggests that curcumin together with available therapies can generate a synergistic action achieved through multiple molecular targeting, which results in simultaneous inhibition of tumor growth, and reduced treatment-induced toxicity as well as resistance. The review also highlights approaches to increase bioavailability and bioaccumulation of drugs when co-delivered with curcumin using nano-cargos. Despite substantial preclinical work on radio-chemo sensitizing effects of curcumin, to date, there is only a single clinical report on brain tumors. Based on available lab evidence, it is proposed that antibody-conjugated nano-curcumin in combination with sub-toxic doses of conventional or repurposed therapeutics should be designed and tested in clinical studies. This will increase tumor targeting, the bioavailability of the drug combination, reduce therapy resistance, and tumor recurrence through modulation of aberrant signaling cascades; thus improving clinical outcomes in brain malignancies.

Keywords: Glioblastoma; combination therapy; polyphenol; resistance; sensitization; synergistic.

Fig.1

Schematic representation of Curcumin the pleiotropic molecule, as a sensitizer and adjunct to conventional treatment modalities. Level 1 depicts conventional therapies categorized on the basis of their individual action. Level 2 indicates the molecules and pathways targeted in the presence of CUR as the sensitizer. Level 3 specifies the cellular endpoints, and level 4 presents the expected clinical outcomes. ACNU : nimustine; BCNU: carmustine; Bax: Bcl-2-associated X protein; BAD: Bcl-2-associated death promoter; Bcl-2: B-cell lymphoma 2; bFGF: basic fibroblast growth factor; Cyt c: cytochrome-c; Dox: doxorubicin; DNA: deoxyribonucleic acid; EMT: epithelial to mesenchymal transition; GLI1: glioma-associated oncogene homolog 1; hTERT: human telomerase reverse transcriptase; JAK/STAT3: Janus kinases/signal transducer and activator of transcription 3; MMP: matrix metalloproteinases, mTOR: mammalian target of rapamycin; NFκB: nuclear factor kappa-light-chain-enhancer of activated B-cells; PI3K/Akt: phosphatidylinositol 3-kinases/ protein kinase B, PTX: paclitaxel; TMZ: temozolamide; ROS: reactive oxygen species; Sufu: suppressor of fused homolog; Shh: sonic hedgehog; Smo: smoothened homolog precursor; VEGF: vascular endothelial growth factor. ↓ (induction); ┴ (inhibition)