Sarma Ashapurna, Sharma Vishal P, Sarkar Arindam B, Sekar M Chandra, Samuel Karunakar, Geusz Michael E
Department of Biological Sciences, Bowling Green State University, 217 Life Science Building, Bowling Green, OH, 43403, USA.
Life Sciences Institute, University of Michigan, Ann Arbor, MI, 48109, USA.
BMC Cancer. 2016 Sep 29;16(1):759. doi: 10.1186/s12885-016-2789-9.
Curcuminoids of the spice turmeric and their enhanced derivatives have much potential as cancer treatments. They act on a wide variety of biological pathways, including those regulating cell division and circadian rhythms. It is known that circadian clocks can modify cancer therapy effectiveness, according to studies aimed at optimizing treatments based on the circadian cycle. It is therefore important to determine whether treatments with curcumin or similar chemotherapeutic agents are regulated by circadian timing. Similarly, it is important to characterize any effects of curcumin on timing abilities of the circadian clocks within cancer cells.
We examined the circadian clock's impact on the timing of cell death and cell division in curcumin-treated C6 rat glioma cells through continuous video microscopy for several days. To evaluate its persistence and distribution in cancer cells, curcumin was localized within cell compartments by imaging its autofluorescence. Finally, HPLC and spectroscopy were used to determine the relative stabilities of the curcumin congeners demethoxycurcumin and bisdemethoxycurcumin that are present in turmeric.
Circadian rhythms in cell death were observed in response to low (5 μM) curcumin, reaching a peak several hours before the peak in rhythmic expression of mPER2 protein, a major circadian clock component. These results revealed a sensitive phase of the circadian cycle that could be effectively targeted in patient therapies based on curcumin or its analogs. Curcumin fluorescence was observed in cell compartments at least 24 h after treatment, and the two congeners displayed greater stability than curcumin in cell culture medium.
We propose a mechanism whereby curcuminoids act in a sustained manner, over several days, despite their tendency to degrade rapidly in blood and other aqueous media. During cancer therapy, curcumin or its analogs should be delivered to tumor cells at the optimal phase for highest efficacy after identifying the circadian phase of the cancer cells. We confirmed the greater stability of the curcumin congeners, suggesting that they may produce sustained toxicity in cancer cells and should be considered for use in patient care.
姜黄中的姜黄素类化合物及其增强衍生物在癌症治疗方面具有很大潜力。它们作用于多种生物途径，包括调节细胞分裂和昼夜节律的途径。根据旨在基于昼夜节律周期优化治疗的研究，已知生物钟可改变癌症治疗效果。因此，确定姜黄素或类似化疗药物的治疗是否受昼夜节律调控很重要。同样，表征姜黄素对癌细胞内生物钟计时能力的任何影响也很重要。
我们通过连续几天的视频显微镜观察，研究了生物钟对姜黄素处理的C6大鼠胶质瘤细胞中细胞死亡和细胞分裂时间的影响。为了评估其在癌细胞中的持久性和分布，通过对姜黄素自身荧光成像将其定位在细胞区室中。最后，使用高效液相色谱法和光谱法测定姜黄中存在的姜黄素同系物去甲氧基姜黄素和双去甲氧基姜黄素的相对稳定性。
在低浓度（5 μM）姜黄素作用下观察到细胞死亡的昼夜节律，在主要生物钟成分mPER2蛋白节律性表达高峰前数小时达到峰值。这些结果揭示了昼夜节律周期的一个敏感阶段，在基于姜黄素或其类似物的患者治疗中可有效靶向该阶段。处理后至少24小时在细胞区室中观察到姜黄素荧光，并且这两种同系物在细胞培养基中比姜黄素表现出更高的稳定性。
我们提出了一种机制，即尽管姜黄素类化合物在血液和其他水性介质中倾向于快速降解，但它们仍能持续作用数天。在癌症治疗期间，在确定癌细胞的昼夜节律阶段后，应在最佳阶段将姜黄素或其类似物递送至肿瘤细胞以获得最高疗效。我们证实了姜黄素同系物具有更高的稳定性，表明它们可能在癌细胞中产生持续毒性，应考虑用于患者护理。
