Circadian rhythm could influence chemotherapy success

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Doctors often wonder if there is a best time of day for cancer patients to receive chemotherapy. Past research suggests there probably is an optimal time based on the body's circadian rhythms. Now a compelling new study offers some biological proof for the idea.

The study, conducted in mice, found that the ability to repair damage was at a minimum in the early morning and reached a peak in the evening.

The researchers say their study needs to be replicated in humans and that they plan to explore whether their findings can apply to skin cancer prevention. Showing the same patterns in humans could suggest the safest time for sun exposure, the senior author of the paper, Dr. Aziz Sancar, said in a news release.

The study will be published this week in the online early edition of the Proceedings of the National Academy of Sciences.

Full story http://www.latimes.com/news/science/...tory?track=rss

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Re: Circadian rhythm could influence chemotherapy success

Additional info from MedicalNewsToday

The findings could enable clinicians to reset the internal clock of each cancer cell to render it more vulnerable to attack with chemotherapeutic drugs.

"Adjusting the clock in this way could certainly be a new target for cancer treatment," said senior study author Aziz Sancar, M.D., Ph.D., a member of the UNC Lineberger Comprehensive Cancer Center and Sarah Graham Kenan Professor of Biochemistry and Biophysics in the UNC School of Medicine. Sancar is also a member of the National Academy of Sciences, the Turkish Academy of Sciences and the American Academy of Arts and Sciences.

While altering the clock gene did not cause cancer in otherwise normal mice, Sancar and his colleagues wanted to see if it would accelerate the development of tumors in a mouse model that is already predisposed to cancer. Therefore, in this study they modified the cryptochrome gene in mice that also had defects in a gene called P53, which is mutated in nearly half of human cancers. The researchers found that disturbing the internal clock in these mice did not speed up the onset of cancer, but instead had the opposite effect - it extended their lives by 50 percent.

The researchers then wanted to know how interfering with the cryptochrome gene had reduced the incidence of cancer. By closely examining the series of biological events in the disease's development, they determined that the mutation of this clock gene reactivates the intracellular signals that can eliminate cancerous cells. Sancar said this tactic essentially makes cancer cells more likely to commit cell suicide - through a process known as apoptosis - in response to the stresses of UV radiation or chemotherapy.

"These results suggest that altering the function of this clock gene, at least in the 50 percent of human cancers associated with p53 mutations, may slow the progression of cancer," Sancar said. "In combination with other approaches to cancer treatment, this method may one day be used to increase the success rate of remission."

The study follows the recent publication earlier this month of another paper from Sancar's laboratory in the Proceedings of the National Academy of Sciences. It suggested that chemotherapy treatment for cancer is most effective at certain times of day because that is when a particular enzyme system - one that can reverse the actions of chemotherapeutic drugs - is at its lowest levels in the body.

Read more: http://www.medicalnewstoday.com/articles/137859.php

Link to the abstract at PNAS http://intl.pnas.org/content/early/2...2-5710497b78d6

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Re: Circadian rhythm could influence chemotherapy success

Entrainment of breast (cancer) epithelial cells detects distinct circadian oscillation patterns for clock and hormone receptor genes
Rossetti S, Esposito J, Corlazzoli F, Gergorski A, Sacchi N.
Source
Abstract

Most physiological and biological processes are regulated by endogenous circadian rhythms under the control of both a master clock, which acts systemically and individual cellular clocks, which act at the single cell level. The cellular clock is based on a network of core clock genes, which drive the circadian expression of non-clock genes involved in many cellular processes.

Circadian deregulation of gene expression has emerged to be as important as deregulation of estrogen signaling in breast tumorigenesis. Whether there is a mutual deregulation of circadian and hormone signaling is the question that we address in this study. Here we show that, upon entrainment by serum shock, cultured human mammary epithelial cells maintain an inner circadian oscillator, with key clock genes oscillating in a circadian fashion. In the same cells, the expression of the estrogen receptor α (ER A) gene also oscillates in a circadian fashion. In contrast, ER A-positive and -negative breast cancer epithelial cells show disruption of the inner clock.

Further, ER A-positive breast cancer cells do not display circadian oscillation of ER A expression. Our findings suggest that estrogen signaling could be affected not only in ER A-negative breast cancer, but also in ER A-positive breast cancer due to lack of circadian availability of ER A. Entrainment of the inner clock of breast epithelial cells, by taking into consideration the biological time component, provides a novel tool to test mechanistically whether defective circadian mechanisms can affect hormone signaling relevant to breast cancer.

http://www.ncbi.nlm.nih.gov/pubmed/22193044?dopt=Abstract

Circadian function in cancer: Regulating the DNA damage response
Matthew R. Ramsey and Leif W. Ellisen
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These findings may have particular implications for the field of cancer chronotherapy, which seeks to determine whether the effectiveness and tolerability of chemotherapy can be linked to the time of day treatment is given. Indeed, it has been found that treatment schedule can impact both long-term survival and nonspecific toxicity (9, 10). However, the widespread application of such observations to standard clinical practice has been hampered by a lack of insight into how the circadian cycle influences the response to specific chemotherapeutic agents. The new study demonstrates that p53-deficient tumor cells with compromised circadian function exhibit increased apoptosis and slower tumor growth in vivo after treatment with oxaliplatin (3). The finding that this effect is linked to p73 supports previous studies showing that platinum agents induce apoptosis at least in part through phosphorylation-dependent activation of TAp73 (11, 12) and that TAp73 levels are a key determinant of chemosensitivity (6, 13).
Full Study: http://intl.pnas.org/content/108/26/10379.full