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Chronopharmacology of cisplatin: Role of the circadian rhythm in modulating the cisplatin transporters levels
Author(s) -
Sorensen Daniel N.,
Dakup Panshak P.,
Gaddameedhi Shobhan
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.935.1
Subject(s) - circadian rhythm , per1 , cisplatin , pharmacology , biology , endocrinology , medicine , kidney , circadian clock , clock , chemotherapy
Purpose Cisplatin is one of the most commonly used chemotherapeutic drugs in treating a variety of tumors including cancers of ovaries, testis, lungs, blood and solid tumors of the head and neck. However, the major limitation of cisplatin as a chemotherapeutic drug is due to tumor resistance and nephrotoxicity. The main focus of our project was to study the chronopharmacologic effects that have been demonstrated in human models of cisplatin chemotherapy showing decreased renal toxicity and side effects. We hypothesized a mechanistic, circadian rhythm‐based cause for these outcomes. To further evaluate our hypothesis, we have screened the expression levels of all known cisplatin transporters (both influx and efflux) as well as the cisplatin‐DNA repair activity as a function of the circadian rhythm. Experimental Design Studies were done on mouse models of wild‐type and circadian disrupted Per1/2 − / − animals from tissues samples (kidney and liver) taken at different circadian time points and compared via qRT‐PCR analysis for RNA expression along with the same study with human blood samples by the time of day in a 24‐hour period. In case of cisplatin‐DNA repair activity as a function of the circadian rhythm, immuno‐slot blot assays were performed. Results Data from kidney tissue RNA samples showed possible clock controlled transporter expression in wild‐type animals as compared to Per1/2 − / − including OCT2, MRP1 (GS‐X) and ATP7A. These mice showed higher expression during the evening hours compared to the morning hours. This was also seen in fresh samples of human blood where the expression levels of these transporters were in opposite phase to mouse tissues. In addition to the circadian variation on expression levels of the above transporters, our findings suggest that cisplatin‐DNA repair function might also be regulated by the time of day in mouse kidney. Conclusions These findings indicate a possible mechanism for the chronopharmacology of cisplatin in minimizing the toxicity associated with it and reveal a target for future study of additional mechanistic causes of circadian dosing changes in cisplatin and other medications. Support or Funding Information WSU College of Pharmacy Start‐up Funds