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A systematic assessment of chemical, genetic, and epigenetic factors influencing the activity of anticancer drug KP1019 (FFC14A).

ABSTRACT: KP1019 ([trans-RuCl4(1H-indazole)2]; FFC14A) is one of the promising ruthenium-based anticancer drugs undergoing clinical trials. Despite the pre-clinical and clinical success of KP1019, the mode of action and various factors capable of modulating its effects are largely unknown. Here, we used transcriptomics and genetic screening approaches in budding yeast model and deciphered various genetic targets and plethora of cellular pathways including cellular signaling, metal homeostasis, vacuolar transport, and lipid homeostasis that are primarily targeted by KP1019. We also demonstrated that KP1019 modulates the effects of TOR (target of rapamycin) signaling pathway and induces accumulation of neutral lipids (lipid droplets) in both yeast and HeLa cells. Interestingly, KP1019-mediated effects were found augmented with metal ions (Al3+/Ca2+/Cd2+/Cu2+/Mn2+/Na+/Zn2+), and neutralized by Fe2+, antioxidants, osmotic stabilizer, and ethanolamine. Additionally, our comprehensive screening of yeast histone H3/H4 mutant library revealed several histone residues that could significantly modulate the KP1019-induced toxicity. Altogether, our findings in both the yeast and HeLa cells provide molecular insights into mechanisms of action of KP1019 and various factors (chemical/genetic/epigenetic) that can alter the therapeutic efficiency of this clinically important anticancer drug.

SUBMITTER: Golla U

PROVIDER: S-EPMC5716741 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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A systematic assessment of chemical, genetic, and epigenetic factors influencing the activity of anticancer drug KP1019 (FFC14A).

Golla Upendarrao U Swagatika Swati S Chauhan Sakshi S Tomar Raghuvir Singh RS

Oncotarget 20170930 58

KP1019 ([trans-RuCl<sub>4</sub>(1H-indazole)<sub>2</sub>]; FFC14A) is one of the promising ruthenium-based anticancer drugs undergoing clinical trials. Despite the pre-clinical and clinical success of KP1019, the mode of action and various factors capable of modulating its effects are largely unknown. Here, we used transcriptomics and genetic screening approaches in budding yeast model and deciphered various genetic targets and plethora of cellular pathways including cellular signaling, metal ho ...[more]

PMID: 29228701

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Project description:BackgroundNon-adherence is widespread problem. Adherence is a crucial point for the success and the safe use of therapies. The objective of this overview (review of reviews) was to identify factors that influence adherence in chronic physical conditions.MethodsA systematic literature search was performed in Medline and Embase (1990 to July 2013). Publications were screened according to predefined inclusion criteria. The study quality was assessed using AMSTAR. Both process steps were carried out independently by two reviewers. Relevant data on study characteristics and results were extracted in piloted standardized tables by one reviewer and checked by a second. Data were synthesized using a standardized quantitative approach by two reviewers.ResultsSeven systematic reviews were included. Higher education and employment seem to have a positive effect on adherence. Ethnic minorities seem to be less adherent. Co-payments and higher medication cost seems to have negative effect on adherence. In contrast financial status/income and marital status seem to have no influence on adherence. The effect of therapy related factors was mostly unclear or had no effect. Only the number of different medications in heart failure patients showed the tendency of an effect. Indicators of regime complexity showed consistently a negative effect direction. Duration of disease seems to have no effect on adherence. There is the tendency that higher or middle age is associated with higher adherence. But in more than half of the reviews the effect was unclear. There is no clear effect of physical as well as mental comorbidity. Only one review showed the tendency of an effect for mental comorbidity. Also for gender the effect is not clear because the effect direction was heterogenic between and within the systematic reviews.ConclusionThe presented overview shows factors than can potentially have influence on adherence. Only for a few factors the influence on adherence was consistent. Most factors showed heterogeneous results regarding statistical significance and/or effect direction. However, belonging to an ethnic minority, unemployment and cost for the patient for their medications showed consistently a negative effect on adherence which indicates that there is a social gradient.

Dataset Information

A systematic assessment of chemical, genetic, and epigenetic factors influencing the activity of anticancer drug KP1019 (FFC14A).

Publications

A systematic assessment of chemical, genetic, and epigenetic factors influencing the activity of anticancer drug KP1019 (FFC14A).

Similar Datasets

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