The circadian clock modulates anti-cancer properties of curcumin.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Biological Sciences, Bowling Green State University, 217 Life Science Building, Bowling Green, OH, 43403, USA.
Ashapurna
A
Sarma
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.
Vishal P
VP
Sharma
Department of Pharmaceutical Sciences, University of Findlay, Findlay, OH, 45840, USA.
Arindam B
AB
Sarkar
Department of Pharmaceutical Sciences, University of Findlay, Findlay, OH, 45840, USA.
M Chandra
MC
Sekar
Department of Biological Sciences, Bowling Green State University, 217 Life Science Building, Bowling Green, OH, 43403, USA.
Karunakar
K
Samuel
Department of Biological Sciences, Bowling Green State University, 217 Life Science Building, Bowling Green, OH, 43403, USA. mgeusz@bgsu.edu.
Michael E
ME
Geusz
Apoptosis; Cell cycle; Chronopharmacology; Circadian rhythm; Curcumin; Curcuminoids; Glioma
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