Interaction Analysis of MRP1 with Anticancer Drugs Used in Ovarian Cancer: In Silico Approach.

Multidrug resistance (MDR) is one of the major therapeutic challenges that limits the efficacy of chemotherapeutic response resulting in poor prognosis of ovarian cancer (OC). The multidrug resistance protein 1 (MRP1) is a membrane-bound ABC transporter involved in cross resistance to many structurally and functionally diverse classes of anticancer drugs including doxorubicin, taxane, and platinum. In this study, we utilize homology modelling and molecular docking analysis to determine the binding affinity and the potential interaction sites of MRP1 with Carboplatin, Gemcitabine, Doxorubicin, Paclitaxel, and Topotecan. We used AutoDock Vina scores to compare the binding affinities of the anticancer drugs against MRP1. Our results depicted Carboplatin < Gemcitabine < Topotecan < Doxorubicin < Paclitaxel as the order of binding affinities. Paclitaxel has shown the highest binding affinity whereas Carboplatin displayed the lowest affinity to MRP1. Interestingly, our data showed that Carboplatin, Paclitaxel, and Topotecan bind specifically to Asn510 residue in the transmembrane domains 1 of the MRP1. Our results suggest that Carboplatin could be an appropriate therapeutic choice against MRP1 in OC as it couples weakly with Carboplatin. Further, our findings also recommend opting Carboplatin with Gemcitabine as a combinatorial chemotherapeutic approach to overcome MDR phenotype associated with recurrent OC.

MDR1 Gene Polymorphisms and Its Association With Expression as a Clinical Relevance in Terms of Response to Chemotherapy and Prognosis in Ovarian Cancer.

In spite of the significant advancements in the treatment modalities, 30% of advanced stage ovarian cancer (OC) patients do not respond to the standard chemotherapeutic regimen and most of the responders finally relapse over time due to the escalation of multidrug resistance (MDR) Phenomenon. Our present study evaluated chemotherapeutic sensitivity response among 47 ovarian tumor patients of which we found 37 (78.8%) sensitive and remaining 10 (21.2%) resistant. Among the resistant, seven tumor samples were found to be platinum resistant or refractory to platinum (CB/TX), one to carboplatin, and two to 5FU. Notably, all these resistant cases were observed in the disease recurrence group of patients identified at stage III or IV. The stage III resistant cases revealed heterozygous mutation (C/T) in exon 12 (C1236T) and 26 (C3435T) and increased level of mRNA, whereas homozygous mutation (T/T) was found at stage IV tumor patients. The genotypic difference was found to be significant (p = 0.03) for exon 12, and p = 0.003 for exon 26 mutant genotypes. No significant association between genotypes of different exons with tumor stages and tumor grade was observed (p > 0.05). However, a significant association was observed between the genotype of exon-12 and histopathology of tumor tissue (p = 0.028). Statistically, the chemotherapy response was found to be significantly associated with the tumor stage (p = 0.019). We also observed a significant difference in PFS (P = 0.019) and OS (P = 0.047) between tumor grades 1 and 3. Notably, the highest mRNA expression was observed in resistant tumor sample T-32, where interestingly we found homozygosity TT in all of the exons 12, 21, and 26. Thus, we suggest that exons 12 (C1236T) and exon 26 (C3435T) polymorphism may play a role in inducing drug resistance by altering the expression level of the MDR1 gene. To summarize, we suggest that the expression of MDR1 in OC is influenced by tumor stage and genotype variants as well as by chemotherapeutic drugs. Thus our findings suggest that inter individual variability in platinum based therapy may be anticipated by MDR1 genotypes. Further studies on a large number of samples shall eventually lead to provide beneficial information for the individualized chemotherapy.

Molecular docking analysis of HER-2 inhibitor from the ZINC database as anticancer agents.

The human epidermal growth factor (HER2) is a transmembrane receptor that is highly expressed in breast cancer and in different other cancers. Therefore, it is of interest to identify the new HER2 inhibitors from a selected 300 compounds in the ZINC database. The top two hit compounds (ZINC000014780728 (-11.0 kcal/mol) and ZINC000014762512 (-10.8 kcal/mol)) showed a high affinity with HER2 relative to the reference compound (lapatinib (-10.2 kcal/mol)) for further consideration.

Structure-based virtual screening and molecular docking for the identification of potential novel EGFRkinase inhibitors against ovarian cancer.

Epidermal Growth Factor Receptor (EGFR) is, for the most part, deregulated and over-communicated in ovarian disease, which is legitimately connected with STAT3 enactment that prompts the collection of hostile to apoptotic occasions and along these lines, docetaxel medicate obstruction happens. As to, expanding of docetaxel medicate affectability by focusing on EGFR receptor alongside docetaxel drugs is one of the real techniques in ovarian disease treatment. In this specific circumstance, utilizing atomic recreation considers, the present examination depicted the auxiliary and pragmatic properties of IBS Database mixes as a potential inhibitor of EGFR tyrosine kinase, and furthermore ADMET had researched its Pharmacokinetic profile. As indicated by the outcomes, STOCK1N-98911, STOCK1N- 98869, and STOCK1N-98896 have appeared tremendous restricting vitality by associating with critical build ups in the dynamic site. Natural movement range forecast of these mixes indicated potential anticancer properties by demonstrating important collaboration with EGFR tyrosine kinase. Besides, the investigation is likewise valuable for further clinical based examinations and furthermore for the approval of toxicological and pharmacokinetic contemplate.

Translational Shift of HSP90 as a Novel Therapeutic Target from Cancer to Neurodegenerative Disorders: An Emerging Trend in the Cure of Alzheimer's and Parkinson's Diseases.

BACKGROUND: Despite having extensive research, the apparent pathogenic mechanism of Alzheimer's disease (AD), Parkinson's disease (PD) and other neurodegenerative diseases (NDs) have not yet fully understood. The Heat Shock Protein 90 (HSP90), a ubiquitous molecular chaperone, found to have an important role in averting protein misfolding and aggregation through inhibition of apoptotic activity in neuro-inflammatory diseases. Various researchers have confirmed its role in maintaining aberrant neuronal protein's functional stability to a great capacity. It is also involved in regulating the activity of the heat shock factor-1 (HSF-1), a vital regulator of the heat shock response mechanism that cells employ to protect themselves against stress conditions. This quality makes the HSP90 an ideal candidate for novel inhibitory target for therapeutic modality in NDs. METHODS: An extensive literature search was conducted for relevant studies on PubMed, ScienceDirect, Springer- Link etc. The articles were carefully read in their entirety to determine whether they contained information on the topic of interest. Additionally, the reference sections of these articles were searched manually to get more relevant and eligible studies. RESULTS: We have taken an attempt to reveal how HSP90 play important roles with key neuronal proteins involved in supporting the AD and PD pathology. We have further on structure-function relationship of HSP90 to understand its efficacy as a new target in AD and PD by utilizing new generation of HSP90 inhibitors such as geldanamycin and its derivatives, 17-AAG, 17-DMAG, IPI-504, radicicol and its derivatives. HSP90 inhibition leads to suppress atypical neuronal activity by assisting in improving protein aggregation and its related toxicity. Further, the formation of neuronal aggregates is also influenced by HSP90 inhibitors and provides protection from toxicity of protein through HSF-1 activation and HSP70 induction in AD. CONCLUSION: HSP90 inhibition has emerged as a potential target in treating diverse array of diseases especially NDs. In spite of a large amount of research in this direction, the clear cut molecular mechanisms of HSPs associated with neuroprotection are still poorly elucidated and hence more focus is needed toward HSPs and its inhibitory mechanism. The development of HSP90 inhibitors that induce heat-shock response without cytotoxicity for treatment of NDs are still in its early stage. A panel of novel designed research and clinical trial studies are greatly needed to establish the therapeutic reliability and efficacy of HSPs in order to provide best cure for NDs.

Current Understanding of HSP90 as a Novel Therapeutic Target: An Emerging Approach for the Treatment of Cancer.

Heat Shock Protein 90 (HSP90) is a ubiquitous molecular chaperone that is considered to be the most abundantly expressed protein in various human cancers such as breast, lung, colon, prostate, leukemia and skin. The master regulator, HSP90 plays a pivotal role in the conformational stabilization, maturation and activity of its various labile oncogenic client proteins such as p53, ErbB2, Bcr-Abl, Akt, Her-2, Cdk4, Cdk6, Raf-1 and v-Src in altered cells. Hence, making a guaranteed attempt to inhibit such a master regulator for cancer therapy appears to be a potential approach for combinatorial inhibition of numerous oncogenic signaling pathways simultaneously. Considerable efforts are being under way to develop novel molecular targets and its inhibitors that may block key signaling pathways involved in the process of tumorigenesis and metastasis. In this regards, HSP90 has acquired immense interest as a potent anticancer drug-target due to its key functional link with multiple signaling pathways involved in the process of cell proliferation and cell survival. Notably, geldanamycin and its derivatives (17-AAG, 17-DMAG) have shown quite encouraging results in inhibiting HSP90 function in several cancers and currently almost 17 drug candidates known to be target HSP90 are being under clinical trials either as single agents or combinatorial therapy. Hence, this review is an attempt to get new insight into novel drug target therapy by focusing on recent advances made in understanding HSP90 chaperone structure-function relationships, identification of new HSP90 client proteins and, more importantly, on the advancements of HSP90 targeted therapy based on various existing and emerging classical inhibitors.