Over 36,000 people in the United States will be diagnosed with hepatocellular carcinoma (HCC) in 2016, the second leading cause of cancer death worldwide. Metabolic pathways within the liver and in HCC are highly regulated by the central circadian clock in the suprachiastmatic nucleus (SCN). The SCN drives nighttime production of the circadian anti-cancer hormone melatonin by the pineal gland in rats and humans. We have shown that the nighttime circadian melatonin signal suppresses the Warburg effect (aerobic glycolysis) in human breast cancer xenografts and that blue-enriched light (460-480 nm) from LEDs at daytime (bLAD), amplifies the nighttime circadian melatonin signal by 7-fold in rats over cool white fluorescent (CWF) lighting. Here we tested whether daytime exposure of tissue-isolated HepG2 xenograft-bearing male nude rats to bLAD amplifies the nighttime melatonin signal to increase tumor sensitivity to nighttime administered sorafenib (FDA-approved multi-kinase inhibitor) treatment via enhancing suppression of the Warburg effect. Animals were randomized to 6 subgroups (n = 4): CWF Groups I, 12 h light:12 h dark (LD,12:12) (CWF + vehicle) and II (CWF + sorafenib); bLAD Groups III (LD,12bLAD:12) (bLAD + vehicle), IV (bLAD + sorafenib), V (bLAD + S20928 MT1/MT2 receptor blocker), and VI (bLAD + S20928 + sorafenib). Drug treatments began when tumors were 2.5 g estimated weight. Plasma nighttime melatonin levels were 7-fold higher in Groups III-VI, compared to Groups I and II. Tumor latency-to-onset of growth and growth rates were markedly delayed and decreased, respectively, in Group III compared to Group I. Sorafenib induced tumor regression at a rate that was 2-fold higher in the bLAD- vs CWF-exposed rats. Tumor glucose uptake and lactate production (Warburg effect) at the mid-dark phase were significantly reduced in CWF-exposed rats receiving sorafenib vs vehicle. In vehicle-treated bLAD-exposed rats, the Warburg effect was significantly decreased vs CWF-exposed rats receiving vehicle. In bLAD + sorafenib-treated rats, the Warburg effect was reduced by an additional 51% (glucose uptake) and 89% (lactate production), respectively, vs CWF + sorafenib-treated rats. Melatonin receptor blocker S20928 completely prevented the effects of bLAD and bLAD + sorafenib on the Warburg effect and made these tumors completely resistant to sorafenib-induced tumor regression. These findings are the first to show in vivo that: 1) nighttime circadian sorafenib therapy inhibited the Warburg effect and induced HepG2 tumor regression under CWF lighting conditions, and 2) the bLAD-amplified nocturnal circadian melatonin signal increased tumor sensitivity to sorafenib-induced regression by enhancing a melatonin receptor-mediated suppression of the Warburg effect.
Citation Format: Robert T. Dauchy, David T. Pointer, Aaron E. Hoffman, Melissa A. Wren-Dail, Shulin Xiang, Lin Yuan, David E. Blask, Victoria P. Belancio, Steven M. Hill. Daytime blue-enriched LED light-induced circadian amplification of the nighttime melatonin signal increases sorafenib sensitivity in human hepatocellular carcinoma via enhanced suppression of the Warburg effect [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3191. doi:10.1158/1538-7445.AM2017-3191