In vitro Anti-Cancer Activity of Rosuvastatin and Ketorolac Nanoformulations against DDX3

Abstract

INTRODUCTIONHuman DDX3 gene encodes a polypeptide of 662 amino acids and this protein plays an important role in several aspects of RNA metabolism. 1,2 This protein has two clear distinguishable domains comprised of N-terminal DEAD box domain 1 (211-403 residues) and C-terminal helicase domain 2 (411-575 residues). Both domains displayed RecA-like folds comprising a central β-sheet flanked by α-helices connected by a noncanonical linker of 11 amino acids.3 Expression of DDX3 was detected in several tissues such as testis, colon, lung, liver, skeletal muscle, and kidney 2,4 indicating the universal role of DDX3 in cellular homeostasis. Moreover, elevated expression of DDX3 was found in a highly aggressive metastatic breast cancer cell line, MDA-MB-231, as compared with non-metastatic MCF-7 cells, which show its potential role in aggressive breast cancers and associated metastasis. 5,6 We have previously reported that overexpression of DDX3 in immortalized non-turmorigenic MCF10A cells promoted neoplastic transformation as indicated by down regulation of a cell adhesion molecule, E-cadherin.5 Down-regulation of E-cadherin is a common feature of a variety of metastatic epithelial tumors, including those of the lung, breast and prostate cancer.5,7-9 Hypoxic regions of solid tumors were considered to be the primary sites for the generation of the metastatic phenotype and have been demonstrated to be chemo and radio-resistant. [10][11][12][13][14] We have also reported that hypoxia inducible factor (HIF-1) induce the expression of DDX3 in two different breast cell lines by binding directly or indirectly to the hypoxia-response element (HRE) in the DDX3 proximal promoter. 15 On the other hand, a significant down regulation of DDX3 expression is found in hepatocellular carcinoma (HCCs) from the hepatitis B virus (HBV) positive patients, but not from HCV positive in comparison to the corresponding non tumor tissues. 16 In the hepatocellular carcinoma model, DDX3 was found to act as a tumor suppressor by activating the expression of cyclin dependent kinase inhibitor p21 cip1 . 17 Besides cancer, induced expression of DDX3 was also found in HIV-1 infected cells. 18,19 Overall, it suggests that DDX3 is a multifunctional protein and it plays a specific role in regulatory mechanisms and signaling pathways. Apart from embryonic development, this gene is also involved in multiple diseases like HIV, Neuro-degenerative diseases, hepatocellular carcinoma and brain and breast cancer. Several Synthetic compounds have been discovered to inhibit the function of DDX3 by blocking the function of helicase activity. [20][21][22][23][24] Synthetic drugs are those substances that are produced entirely from chemical reactions in a laboratory. Synthetic drugs most often have shown to suppress the immune system by paralyzing the bone marrow. 25,26 Moreover, it takes an average of about 8 to 12 years from the time a cancer drug enters into clinical trials from the research lab.27,28 Therefore, we focused to identify FDA approved drugs against D...

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“…Further, subculture was performed when a confluence of 90% was reached. Sulforhodamine B (SRB) assay method was utilized for the in-vitro cytotoxicity of metronidazole and prepared hydrogel formulations (F1and F2) 13 . As per the standard protocol 24 .…”

Quantum Chemical, Molecular Docking, and ADMET Predictions of Ketorolac and its Modified Analogues

“…In vivo selective COX-2 inhibition strategy of Ketorolac drugs is well known for cancer treatments due to their structural diversity, high efficacy, low side effect over other NSAIDs drugs [4,5]. Apart from that, Ketorolac salt also has selective inhibition of DDX3 protein through intra and intermolecular H-bond formation in the diagnosis of several types of cancer [6].…”