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The present study aimed to identify the differentially expressed genes (DEGs) and enriched pathways in docetaxel (DTX) resistant breast cancer cell lines by bioinformatics analysis. The microarray dataset GSE28784 was obtained from gene expression omnibus (GEO) database. The differentially expressed genes (DEGs), gene ontology (GO), and Kyoto Encyclopedia of gene and genome (KEGG) pathway analyses were performed with the help of GEO2R and DAVID tools. Furthermore, the protein–protein interaction (PPI) and hub-gene network of DEGs were constructed using STRING and Cytohubba tools. The prognostic values of hub genes were calculated with the help of the Kaplan–Meier plotter database. From the GEO2R analysis, 222 DEGs were identified of which 120 are upregulated and 102 are downregulated genes. In the PPIs network, five up-regulated genes including CCL2, SPARC, CYR61, F3, and MFGE8 were identified as hub genes. It was observed that low expression of six hub genes CXCL8, CYR61, F3, ICAM1, PLAT, and THBD were significantly correlated with poor overall survival of BC patients in survival analysis. miRNA analysis identified that hsa-mir-16-5p, hsa-mir-335-5p, hsa-mir-124-3p, hsa-mir-20a-5p, and hsa-mir-155-5p are the top 5 interactive miRNAs that are commonly interacting with more hub genes with degree score of greater than five. Additionally, drug-gene interaction analysis was performed to identify drugs which are could potentially elevate/lower the expression levels of hub genes. In summary, the gene-miRNAs-TFs network and subsequent correlation of candidate drugs with hub genes may improve individualized diagnosis and help select appropriate combination therapy for DTX-resistant BC in the future. [ABSTRACT FROM AUTHOR]

Overexpression of cytochrome P450 1B1 in malignancies is accountable for the biotransformation-based inactivation of various chemotherapeutics such as docetaxel, paclitaxel, cisplatin, and tamoxifen. Additionally, it also plays a major role in the development of metabolic disorders including cancer progression, diabetes, obesity, glaucoma, fatty liver, etc. Currently, numerous small molecule inhibitors of this enzyme are being explored to prevent cancer progression and drug resistance problems to the above-mentioned chemotherapeutics. In this work, several benzoxazolinone derivatives have been designed and explored as CYP1B1 inhibitors using various in silico approaches including molecular docking, molecular dynamics (MD), and waterswap analysis. Molecular docking studies revealed that all the designed compounds mimic the crucial active site interactions of the co-crystal ligand, i.e. Alpha naphthoflavone (ANF). To understand the interaction stability of the top four docked compounds, a 100 ns MD analysis was performed. Furthermore, binding free energies of the top docked molecules were computed using three different free energy algorithms, namely Bennet, thermodynamic integration (TI), and free energy perturbation (FEP). The proposed compounds were tested for inhibitory activity towards recombinant human CYP1B1 using an EROD assay. Among them all, compounds R-7 and R-8 were found to be the most promising potent CYP1B1 inhibitors with IC50 values of 0.06 and 0.09 μM, respectively. This research shows that the reported compounds could be used as possible adjuvants with resistance-reversing properties, potentially improving cancer therapy quality. [ABSTRACT FROM AUTHOR]

Resistance against clinically approved anticancer drugs is the main roadblock in cancer treatment. Drug metabolizing enzymes (DMEs) that are capable of metabolizing a variety of xenobiotic get overexpressed in malignant cells, therefore, catalyzing drug inactivation. As evident from the literature reports, the levels of DMEs increase in cancer cells that ultimately lead to drug inactivation followed by drug resistance. To puzzle out this issue, several strategies inclusive of analog designing, prodrug designing, and inhibitor designing have been forged. On that front, the implementation of computational tools can be considered a fascinating approach to address the problem of chemoresistance. Various research groups have adopted different molecular modeling tools for the investigation of DMEs mediated toxicity problems. However, the utilization of these in-silico tools in maneuvering the DME mediated chemoresistance is least considered and yet to be explored. These tools can be employed in the designing of such chemotherapeutic agents that are devoid of the resistance problem. The current review canvasses various molecular modeling approaches that can be implemented to address this issue. Special focus was laid on the development of specific inhibitors of DMEs. Additionally, the strategies to bypass the DMEs mediated drug metabolism were also contemplated in this report that includes analogs and pro-drugs designing. Different strategies discussed in the review will be beneficial in designing novel chemotherapeutic agents that depreciate the resistance problem. [ABSTRACT FROM AUTHOR]

Regardless of continuous research to develop effective chemotherapies and improve patient's prognosis, cancer still remains one of the most deadly diseases worldwide. The reduction in the pace of successfully developing an effective anti-cancer drug is due to the rapid emergence of drug resistance exhibited by tumor cells. One of the resistance mechanisms which is least considered and somewhat overlooked is chemoresistance via drug metabolizing enzymes (DMEs). Therefore, this review emphasizes on pharmacokinetic resistance specifically the DMEs associated chemoresistance, in which drug molecule is rapidly metabolized by DMEs resulting in diminished potential of anti-cancer drugs. The current review will be covering DMEs that are associated with chemoresistance such as ALDH1A1, GST-π, DPD, CYP1B1 and so forth. Although several strategies have been developed to solve this problem such as prodrug designing, analog designing, DMEs inhibitors designing and development of specific pharmaceutical formulations but the inhibition of DMEs is still not considered significantly. Considering the significance of DMEs in chemoresistance, this review shed light on the mechanism of DMEs associated resistance at molecular level, their reported inhibitors that can be used as an adjuvant therapy and strategies (like prodrug designing, analog designing etc.) used so far to combat this problem. [ABSTRACT FROM AUTHOR]