Circadian Timekeeping in Anticancer Therapeutics: An Emerging Vista of Chronopharmacology Research.

BACKGROUND: Intrinsic rhythms in host and cancer cells play an imperative role in tumorigenesis and anticancer therapy. Circadian medicine in cancer is principally reliant on the control of growth and development of cancer cells or tissues by targeting the molecular clock and implementing time-of-day-based anticancer treatments for therapeutic improvements. In recent years, based on extensive high-throughput studies, we witnessed the arrival of several drugs and drug-like compounds that can modulate circadian timekeeping for therapeutic gain in cancer management. OBJECTIVE: This perspective article intends to illustrate the current trends in circadian medicine in cancer, focusing on clock-modulating pharmacological compounds and circadian regulation of anticancer drug metabolism and efficacy. Scope and Approach: Considering the critical roles of the circadian clock in metabolism, cell signaling, and apoptosis, chronopharmacology research is exceedingly enlightening for understanding cancer biology and improving anticancer therapeutics. In addition to reviewing the relevant literature, we investigated the rhythmic expression of molecular targets for many anticancer drugs frequently used to treat different cancer types. Key Findings and Conclusion: There are adequate empirical pieces of evidence supporting circadian regulation of drug metabolism, transport, and detoxification. Administration of anticancer drugs at specific dosing times can improve their effectiveness and reduce the toxic effects. Moreover, pharmacological modulators of the circadian clock could be used for targeted anticancer therapeutics such as boosting circadian rhythms in the host can markedly reduce the growth and viability of tumors. All in all, precision chronomedicine can offer multiple advantages over conventional anticancer therapy.

Phenotypic proteomic profiling identifies a landscape of targets for circadian clock-modulating compounds.

Determining the exact targets and mechanisms of action of drug molecules that modulate circadian rhythms is critical to develop novel compounds to treat clock-related disorders. Here, we have used phenotypic proteomic profiling (PPP) to systematically determine molecular targets of four circadian period-lengthening compounds in human cells. We demonstrate that the compounds cause similar changes in phosphorylation and activity of several proteins and kinases involved in vital pathways, including MAPK, NGF, B-cell receptor, AMP-activated protein kinases (AMPKs), and mTOR signaling. Kinome profiling further indicated inhibition of CKId, ERK1/2, CDK2/7, TNIK, and MST4 kinases as a common mechanism of action for these clock-modulating compounds. Pharmacological or genetic inhibition of several convergent kinases lengthened circadian period, establishing them as novel circadian targets. Finally, thermal stability profiling revealed binding of the compounds to clock regulatory kinases, signaling molecules, and ubiquitination proteins. Thus, phenotypic proteomic profiling defines novel clock effectors that could directly inform precise therapeutic targeting of the circadian system in humans.

Correction: Comprehensive Analysis of Temporal Alterations in Cellular Proteome of Bacillus subtilis under Curcumin Treatment.

[This corrects the article DOI: 10.1371/journal.pone.0120620.].

Chemical characterization and assessment of antioxidant potentiality of Streptocaulon sylvestre Wight, an endangered plant of sub-Himalayan plains of West Bengal and Sikkim.

BACKGROUND: S. sylvestre Wright is an extremely rare plant, found only in the sub-Himalayan Terai region of West Bengal and neighboring Sikkim foot-hills. The plant has never been evaluated for any pharmaceutical properties. The phytochemical status of the plant is still unknown. Therefore, the aim of the study was to explore the antioxidant and free radical scavenging activities and analysis of bioactive compounds present in S. sylvestre. METHODS: S. sylvestre methanolic extract (SSME) was evaluated for different free radical scavenging activities such as hydroxyl radical, nitric oxide, singlet oxygen, hypochlorous acid, peroxynitrite, superoxide radical and hydrogen peroxide scavenging etc. Iron chelating capacity and inhibition of lipid peroxidation were studied in addition to the assessment of haemolytic activity and erythrocyte membrane stabilizing activity (EMSA). Chemical characterization of SSME were performed by high performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS). RESULTS: The results indicate that SSME possess potent antioxidant activity with IC50 value of 113.06 ± 5.67 µg/ml, 63.93 ± 4.16 µg/ml and 142.14 ± 6.13 µg/ml for hydroxyl radical, superoxide radical and hypochlorous acid, respectively. HPLC analysis revealed presence of different phenolic secondary metabolites such as gallic acid, ferulic acid, p-coumaric acid, syringic acid, myricetin, quercetin etc. GC-MS analysis displayed the predominance of γ-sitosterol, vitamin E and squalene in SSME. CONCLUSION: The present study provides a convincing evidence that S. sylvestre not only possess potent antioxidant activity but also can be used as a source of natural bioactive phytochemicals in the future.

Comprehensive analysis of temporal alterations in cellular proteome of Bacillus subtilis under curcumin treatment.

Curcumin is a natural dietary compound with antimicrobial activity against various gram positive and negative bacteria. This study aims to investigate the proteome level alterations in Bacillus subtilis due to curcumin treatment and identification of its molecular/cellular targets to understand the mechanism of action. We have performed a comprehensive proteomic analysis of B. subtilis AH75 strain at different time intervals of curcumin treatment (20, 60 and 120 min after the drug exposure, three replicates) to compare the protein expression profiles using two complementary quantitative proteomic techniques, 2D-DIGE and iTRAQ. To the best of our knowledge, this is the first comprehensive longitudinal investigation describing the effect of curcumin treatment on B. subtilis proteome. The proteomics analysis revealed several interesting targets such UDP-N-acetylglucosamine 1-carboxyvinyltransferase 1, putative septation protein SpoVG and ATP-dependent Clp protease proteolytic subunit. Further, in silico pathway analysis using DAVID and KOBAS has revealed modulation of pathways related to the fatty acid metabolism and cell wall synthesis, which are crucial for cell viability. Our findings revealed that curcumin treatment lead to inhibition of the cell wall and fatty acid synthesis in addition to differential expression of many crucial proteins involved in modulation of bacterial metabolism. Findings obtained from proteomics analysis were further validated using 5-cyano-2,3-ditolyl tetrazolium chloride (CTC) assay for respiratory activity, resazurin assay for metabolic activity and membrane integrity assay by potassium and inorganic phosphate leakage measurement. The gene expression analysis of selected cell wall biosynthesis enzymes has strengthened the proteomics findings and indicated the major effect of curcumin on cell division.