A simple and rapid pre-clinical in vivo model reveals comparative cardiotoxicity profiles of kinase inhibitors.

Despite significant success, targeted therapeutics such as kinase inhibitors (KIs) still pose adverse events such as the cardiotoxicity. There is a lot of variation in the type and intensity of cardiotoxicity caused by different KIs and current pre-clinical models are inadequate to predict it. Thus, there is a need to develop more simple and rapid models for screening of novel KIs at the pre-clinical step itself. We thus aimed to establish a rapid and robust pre-clinical animal model for predicting cardiotoxicity of KIs and identify comparative cardiotoxicity profiles of a panel of FDA-approved KIs. Heart rate measurement and survival analysis of Daphnia was performed at regular intervals following treatment with ten KIs that were approved for the treatment of various cancers. The heart rates of Daphnia as well as the survival varied between KIs in a dose and time dependent manner suggesting differential cardiotoxicity profiles of various KIs. Further, the correlation between the cardiotoxicity and survival also varied among the ten KIs. Importantly, sorafenib and vemurafenib displayed maximum and least cardiotoxicity, respectively. The comparative cardiotoxicity profiles also are in conformity with the previous studies indicating the utility of Daphnia as a valuable and relevant animal model to rapidly predict the cardiotoxicity of novel KIs at a pre-clinical stage.

Estimated sensitivity profiles of lung cancer specific uncommon BRAF mutants towards experimental and clinically approved kinase inhibitors.

Current experimental and clinical data are inadequate to conclusively predict the oncogenicity of uncommon BRAF mutants and their sensitivity towards kinase inhibitors. Therefore, the present study aims at estimating sensitivity profiles of uncommon lung cancer specific BRAF mutations towards clinically approved as well as experimental therapeutics based on computationally derived direct binding energies. Based on the data derived from cBioportal, BRAF mutants displayed significant mutual exclusivity with KRAS and EGFR mutants indicating them as potential drivers in lung cancer. Predicted sensitivity of BRAF-V600E conformed to published experimental and clinical data thus validating the usefulness of computational approach. The BRAF-V600K displayed higher sensitivity to most inhibitors as compared to that of the BRAF-V600E. All the uncommon mutants displayed higher sensitivity than both the wild type and BRAF-V600E towards PLX 8394 and LSN3074753. While V600K, G469R and N581S displayed favorable sensitivity profiles to most inhibitors, V600L/M, G466A/E/V and G469A/V displayed resistance profiles to a variable degree. Notably, molecular dynamic (MD) simulation revealed that increased number of interactions caused enhanced sensitivity of G469R and N581S towards sorafenib. RAF kinase inhibitors were further classified into two groups as per their selectivity (Group I: BRAF-V600E-selective and Group II: CRAF-selective) based on which potential mutation-wise combinations of RAF kinase inhibitors were proposed to overcome resistance. Based on computational inhibitor sensitivity profiles, appropriate treatment strategies may be devised to prevent or overcome secondary drug resistance in lung cancer patients with uncommon mutations.

Cytotoxicity assessment of monocrotophos in Paramecium caudatum and Oxytricha fallax.

Experiments were conducted to evaluate the toxic effects ofmonocrotophos in ciliate models Paramecium caudatum and Oxytricha fallax. In acute toxicity studies higherconcentrations of monocrotophos caused marked increase in mobility of cells exhibiting rocking movements within two mins of exposure but were decreased after 30 mins. LC50 value by mortality curve for 3 hr acute toxicity test of Oxytricha fallax and Paramecium caudatum was found 307.744 +/- 33.27 mg l(-1) and 332.284 +/- 57.52 mg l(-1) respectively. Oxytricha fallax was found sensitive than Paramecium caudatum to monocrotophos. In acute exposure cells showed deformities such as swelling, oval shaped deformity and in higher concentrations shortening of longitudinal axis with blackening of cytoplasm occurred. The length of paramecia was reduced prominently. Similarly enlargement of contractile vacuole and stress egestion of food vacuoles was also observed. The morphological studies showed the changes in shape, size, colour and width of Paramecia and Oxytricha. Frequencies of macronuclear aberrations were significant showing deformities such as rod shaped, elongation, fragmentation, diffusion and total absence of nucleus and were concentration dependent. The data provided in the present study on interaction of pesticides with nuclear structure can be of immense value because most of these pesticides have been reported to have carcinogenic, mutagenic and teratogenic properties.