Circadian rhythms and cancer: implications for timing in therapy

Abstract

Circadian rhythms, intrinsic cycles spanning approximately 24 h, regulate numerous physiological processes, including sleep-wake cycles, hormone release, and metabolism. These rhythms are orchestrated by the circadian clock, primarily located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Disruptions in circadian rhythms, whether due to genetic mutations, environmental factors, or lifestyle choices, can significantly impact health, contributing to disorders such as sleep disturbances, metabolic syndrome, and cardiovascular diseases. Additionally, there is a profound link between the disruption of circadian rhythms and development of various cancer, the influence on disease incidence and progression. This incurred regulation by circadian clock on pathways has its implication in tumorigenesis, such as cell cycle control, DNA damage response, apoptosis, and metabolism. Furthermore, the circadian timing system modulates the efficacy and toxicity of cancer treatments. In cancer treatment, the use of chronotherapy to optimize the timing of medical treatments, involves administering chemotherapy, radiation, or other therapeutic interventions at specific intervals to enhance efficacy and minimize side effects. This approach capitalizes on the circadian variations in cellular processes, including DNA repair, cell cycle progression, and drug metabolism. Preclinical and clinical studies have demonstrated that chronotherapy can significantly improve the therapeutic index of chemotherapeutic agents like cisplatin and 5-fluorouracil by enhancing anticancer activity and reducing toxicity. Further research is needed to elucidate the mechanisms underlying circadian regulation of cancer and to develop robust chronotherapeutic protocols tailored to individual patients' circadian profiles, potentially transforming cancer care into more effective and personalized treatment strategies.

Fig. 1

Role of BMAL1-CLOCK in cancer. This flowchart illustrates the central role of circadian clock proteins BMAL1 and CLOCK in regulating cancer progression through various molecular pathways. BMAL1 activates pro-cancer pathways like c-Myc, Wnt/β-catenin, and Akt/mTOR, promoting tumor growth, progression, and metastasis. Specific cancers, such as liver cancer and intestinal cancer, are influenced by interactions with factors like HNF4-α and TAMs, respectively. On the other hand, the clock protein Rev-ERBα/β acts as an inhibitor of BMAL1, offering potential tumor-suppressive effects. The diagram also highlights the circadian clock’s role in regulating the Unfolded Protein Response (UPR), which impacts tumor survival. Overall, the circadian clock influences both cancer-promoting and inhibiting mechanisms, making it a potential target for therapeutic intervention. Figure created with BioRender.com

Fig. 2

Molecular mechanisms of circadian rhythm. The figure illustrates the central molecular mechanism of the circadian clock, driven by a feedback loop involving key proteins and genes that regulate the body’s 24-h rhythm. The core components are CLOCK and BMAL1, which form a complex in the nucleus and bind to DNA at specific sites to promote the transcription of clock genes like PER (Period) and CRY (Cryptochrome). These genes produce PER and CRY proteins, which accumulate during the night. As PER and CRY proteins build up, they are phosphorylated by CK1δ (Casein Kinase 1 delta) and move into the nucleus, where they inhibit the CLOCK-BMAL1 complex, halting their own production in a negative feedback loop. Over time, the proteins degrade, releasing the inhibition and allowing the cycle to start again the next day. Additional regulators like Rev-Erbα/β and RORs help fine-tune the cycle by controlling BMAL1 expression—Rev-Erbα/β inhibits BMAL1, while RORs promote it. This clock mechanism maintains a roughly 24-h cycle that regulates key processes like sleep–wake cycles, hormone secretion, and metabolism, ensuring alignment with the external day-night cycle. Figure created with BioRender.com

Fig. 3

Impact of circadian clock on cell cycle components. The diagram illustrates the pivotal role of circadian clock proteins CLOCK and BMAL1 in regulating cellular processes such as the cell cycle, DNA repair, and apoptosis. CLOCK and BMAL1 form a heterodimer that initiates the transcription of target genes, including PER2, crucial for maintaining circadian rhythms. This clock influences cell division across the G1, S, G2, and M phases by modulating key proteins like Cyclin B1 and CDK1, with WEE-1 kinase preventing premature entry into mitosis. Additionally, the CLOCK-BMAL1 complex interacts with the p53 pathway, regulating this tumor suppressor in response to DNA damage. The regulation of C-myc by CLOCK and BMAL1 further underscores their dual role in promoting and inhibiting growth. The involvement of Chk2 and ATM proteins in the DNA damage response highlights the interconnectedness of circadian rhythms with cellular stress responses. Overall, the figure emphasizes how the circadian clock ensures cellular integrity and prevents diseases, including cancer, by orchestrating these critical pathways. Figure created with BioRender.com

Fig. 4

Implication of chronotherapeutic approach in improving tolerance and cytotoxicity of anticancer drugs. A Chronotissue tolerance in cancer treatment involves considering the fluctuating levels of key enzymes and biomarkers in host tissues. For instance, dihydropyrimidine dehydrogenase (DPD), responsible for eliminating 5-FU, and thymidine synthase (TS) exhibit opposing peak and trough levels, correlating with decreased toxicity during 5-FU therapy. Additionally, variations in daily levels of glutathione (GSH), a powerful antioxidant, serve as another important biomarker of host chronotolerance, particularly relevant when administering platinum-based drugs like oxaliplatin and cisplatin. Similarly, the efficacy of doxorubicin is more tolerable and highly efficacious in the morning dosage. B Chronotumor toxicity from anticancer agents involves exploiting daily rhythms in the tumor’s cell cycle. Various drugs designed to target specific phases of the cell cycle can be utilized, such as seliciclib for G1 phase, palbociclib for G-S phase transition, 5-FU for S phase, and docetaxel for M phase. Figure created with BioRender.com