Journal
JOURNAL OF NUTRITIONAL BIOCHEMISTRY
Volume 74, Issue -, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jnutbio.2019.108227
Keywords
Curcumin; Regorafenib; Synthetic lethality; Chemosensitivity; MEK inhibition; FDA-approved anticancer drugs
Funding
- National Science Council, Taiwan [101-2313-B-003-002-MY3]
- Ministry of Science and Technology, Taiwan [MOST 104-2320-B-003-007, 105-2320-B-003-003, 106-2320-B-003-006-MY3]
- National Taiwan Normal University, Taiwan [10502, 10602]
- Yuan's General Hospital [RG15-003, YGH 17-002]
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Curcumin, a major yellow pigment and spice in turmeric and curry, has been demonstrated to have an anticancer effect in human clinical trials. Mutation of KRAS has been shown in 35%-45% of colorectal cancer, and regorafenib has been approved by the US FDA to treat patients with colorectal cancer. Synthetic lethality is a type of genetic interaction between two genes such that simultaneous perturbations of the two genes result in cell death or a dramatic decrease of cell viability, while a perturbation of either gene alone is not lethal. Here, we reveal that curcumin significantly enhanced the growth inhibition of regorafenib in human colorectal cancer HCT 116 cells (KRAS mutant) to a greater extent than in human colorectal cancer HT-29 cells (KRAS wild-type), producing an additive or synergistic effect in HCT 116 cells and causing an antagonistic effect in HT-29 cells. Flow cytometric analysis showed that the addition of curcumin elevated apoptosis and greatly increased autophagy in HCT 116 cells but not in HT-29 cells. Mechanistically, curcumin behaved like MEK-specific inhibitor (U0126) to enhance regorafenib-induced growth inhibition, apoptosis and autophagy in HCT 116 cells. Our data suggest that curcumin may target one more gene other than mutant KRAS to enhance regorafenib-induced growth inhibition (synthetic lethality) in colorectal cancer HCT 116 cells, indicating a possible role of curcumin in regorafenib-treated KRAS mutant colorectal cancer. (C) 2019 Elsevier Inc. All rights reserved.
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