Anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) patients are mostly treated with ALK tyrosine kinase inhibitors (TKIs). Crizotinib is the first generation ALK inhibitor practiced as a primary chemo to combat cancer cells followed by second generation inhibitor ceritinib which are effective against crizotinib resistant ALK mutations. However, patients treated with these drugs invariably relapsed because of the development of new drug resistance mutations. In this study we explored the crizotinib resistance in the presence of ALK mutations L1196M and G1269A through molecular dynamics simulation studies. Further mutation specific inhibitors CID 71748211 and CID 71728095 were identified to potentially inhibit ALK with mutations L1196M and G1269A, respectively. This computational investigation in-sighted the molecular factors involved in crizotinib resistance which enhanced in the identification of new ALK drugs that brings individualized medicine to treat ALK positive NSCLC patients with specific mutations. J. Cell. Biochem. 118: 3462-3471, 2017. © 2017 Wiley Periodicals, Inc.

Despite being the most common component of numerous metalloenzymes in the human body, zinc complexes are still under-rated as chemotherapeutic agents. Herein, the present study opens up a key route toward enhanced chemotherapy with the help of two ZnII complexes (ZnMBC) synthesized alongside Mannich base ligands to upsurge biological potency. Further, well-established mesoporous silica nanoparticles (MSNs) have been chosen as carriers of the titled metallodrugs in order to achieve anticancer drug delivery. A pH-sensitive additive, namely, chitosan (CTS) conjugated with biotin is tagged to MSNs for the targeted release of core agents inside tumors selectively. In general, CTS blocks ZnMBC inside the mesopores of MSNs, and biotin acts as a targeting ligand to improve tumor-specific cellular uptake. CTS–biotin surface decoration significantly enhanced the cellular uptake of ZnMBC through endocytosis. A panel of four human cancer cell lines has revealed that ZnMBC (1/2)@MSNs–CTS–biotin nanoparticles (NPs) exhibits unprecedented enhanced cytotoxicity toward cancer cells with IC50 values ranging from 6.5 to 28.8 μM through induction of apoptosis. NPs also possess great selectivity between normal and cancer cells despite this potency. Two-photon-excited in vitro imaging of normal (HEK) and cancer (HeLa) cells has been performed to confirm the biased drug delivery. Also, NP-induced apoptosis was found to be dependent on targeting DNA and ROS generation. Moreover, a lower range of LD50 values (153.6–335.5 μM) were observed upon treatment zebrafish embryos with NPs in vivo. Because of the anatomical similarity to the human heart, the heart rate of NP-treated zebrafish has been analyzed in assessing the cardiac functions, which is in favor of the early clinical trials of ZnMBC (1/2)@MSNs–CTS–biotin candidates for their further evaluation as a chemotherapeutic and chemopreventive agent toward human cancers, especially adenocarcinoma.

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