Cisplatin's dual-effect on the circadian clock triggers proliferation and apoptosis

Abstract

The circadian clock, which generates the internal daily rhythm largely mediated through release of melatonin, can be disrupted in various ways. Multiple factors result in a disruption of the circadian cycle in the clinical context, of interest are anti-cancer drugs such as cisplatin. Cisplatin modulates the circadian clock through two mechanisms: 1) the circadian clock control of DNA excision repair and 2) the effect of circadian clock disruption on apoptosis. Cisplatin can stimulate multiple classified molecules, including DNA repair factors, DNA damage recognition factors and transcription factors in drug resistance and cisplatin-induced signal transduction. These factors interact with each other and can be transformed by DNA damage. Hence, these molecular interactions are intimately involved in cell proliferation and damage-induced apoptosis. Cisplatin has a dual-effect on circadian genes: upregulation of CLOCK expression causes an increase in proliferation but upregulation of BMAL1 expression causes an increase in apoptosis. Therefore, the interference of circadian genes by cisplatin can have multiple, opposing effects on apoptosis and cell proliferation, which may have unintended pro-cancer effects. Melatonin and intracellular Ca 2+ also have a dual-effect on cell proliferation and apoptosis and can disrupt circadian rhythms.

Circadian Rhythms of the Liver and Their Sexual Dimorphism: Current State of the Problem

“…58 Additionally, Ca 2+ and melatonin have also been implicated in the regulation of hepatocyte apoptosis. 59 The CRY mutation activates p53-independent apoptotic pathways in hepatocytes, while the CLOCK gene and neuronal PAS domain protein 2 gene, NPAS2, promote cell proliferation and inhibit mitochondrial apoptosis. 60 While there has been extensive research on the CRs of hepatocytes in animals, 61 there are still several unclear aspects regarding the structure of these rhythms.…”

Systematic Evaluation Meta-Analysis of the Efficacy of Recombinant Human Endostatin Combined with Gemcitabine and Cisplatin in Non-Small-Cell Lung Cancer

“…e growth and diffusion of cancer cells depend on angiogenesis and tumor neogenesis, which is the most important antitumor method of vascular targeted therapy [19,20]. In some studies, NSCLC patients were divided into 34 cases of platinum chemotherapy and 54 cases of platinum plus recombinant human endostatin [21][22][23]. It was found that the progression-free survival rate and overall survival rate of patients treated with combination therapy were significantly improved.…”

Impact of Circadian Rhythms on the Development and Clinical Management of Genitourinary Cancers

“…Combination chemotherapy provides good outcomes initially in impairing tumor growth, but it ultimately fails as cancer cells develop therapeutic resistance ( 87 ). Cisplatin is a first-line chemotherapy treatment that directly interacts with the circadian clock proteins and enhances the body’s natural response to cancerous cells ( 88 ). It upregulates CLOCK and BMAL1, resulting in increased proliferation and increased apoptosis, respectively ( 88 ).…”

“…Cisplatin is a first-line chemotherapy treatment that directly interacts with the circadian clock proteins and enhances the body’s natural response to cancerous cells ( 88 ). It upregulates CLOCK and BMAL1, resulting in increased proliferation and increased apoptosis, respectively ( 88 ). In bladder cancer tissue from human specimens, BMAL1 was downregulated, and CLOCK was upregulated, so cisplatin acts differently on both proteins through unclear mechanisms ( 89 ).…”

“…In bladder cancer tissue from human specimens, BMAL1 was downregulated, and CLOCK was upregulated, so cisplatin acts differently on both proteins through unclear mechanisms ( 89 ). Cisplatin has multiple opposing effects on tumor growth, resulting in stimulating pro-cancer effects ( 88 ). Thus our current understanding begs the question of interrogating the impact of disruption of circadian clock proteins on the molecular mechanisms underlying cell proliferation and apoptosis.…”