Novel Pyrazole-Chalcone Hybrids: Synthesis and Computational Insights Against Breast Cancer.

More women die of breast cancer than of any other malignancy. The resistance and toxicity of traditional hormone therapy created an urgent need for potential molecules for treating breast cancer effectively. Novel biphenyl-substituted pyrazole chalcones linked to a pyrrolidine ring were designed by using a hybridization approach. The hybrids were assessed against MCF-7 and MDA-MB-231 cells by NRU assay. Among them, 8 k, 8 d, 8 m, 8 h, and 8 f showed significantly potent IC50 values: 0.17, 5.48, 8.13, 20.51, and 23.61 µM) respectively, on MCF-7 cells compared to the positive control Raloxifene and Tamoxifen. Furthermore, most active compound 8 k [3-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(2-(2-(pyrrolidin-1-yl)-ethoxy)-phenyl)-chalcone] showed cell death induced through apoptosis, cell cycle arrest at the G2/M phase, and demonstrated decrease of ER-α protein in western blotting study. Docking studies of 8 k and 8 d established adequate interactions with estrogen receptor-α as required for SERM binding. The active hybrids exhibited good pharmacokinetic properties for oral bioavailability and drug-likeness. Whereas, RMSD, RMSF, and Rg values from Molecular dynamics studies stipulated stability of the complex formed between compound 8 k and receptor. All of these findings strongly indicate the antiproliferative potential of pyrazole-chalcone hybrids for the treatment of breast cancer.

Anatomical Description of Anterior Parametrium: A Probable Answer to Pelvic Recurrence Following Radical Hysterectomy.

A prospective analysis of a retrospective data of patients with cervix carcinoma treated by minimal invasive surgery at high-volume gynecology oncology center analyzing that minimal access surgery is an acceptable treatment modality in cervix carcinoma. The study included 423 patients who underwent laparoscopic/robotic radical hysterectomy after pre-operative evaluation after taking their consent and obtaining ethical approval from the IRB. Post-operatively, patients were followed up at regular intervals for clinical examination and ultrasonography for a median range of 36 months. A PET scan was done only if there was any suspicious finding on clinical examination or ultrasonography. Patients with parametrial involvement, positive vaginal margins, and nodal involvement were treated with chemotherapy/radiotherapy. Four hundred twenty-three patients of cervix carcinoma were treated with minimal access surgery. Average duration of surgeries was 92 min. Median range of duration of post-operative follow-up was 36 months. None of the patients had positive resection margins indicating adequate parametrectomy with complete oncological clearance. On post-operative follow-up, only 2 patients had vaginal recurrence which is comparable to that observed in open surgery and no pelvic recurrence. With the understanding of the anatomical landmarks of the anterior parametrium and development of skills for adequate oncological clearance, minimal access surgery should be the preferred surgical modality in carcinoma of the cervix.

Alysicarpus vaginalis Bio-Actives as ESR Signaling Pathway Inhibitor for Breast Cancer Treatment: A Network Pharmacology Approach.

In our previous study Alysicarpus vaginalis (AV) has appeared as a promising target for breast cancer hence we have screened potential targets by in silico, In Vitro and In Vivo methods. A network pharmacology (NP) approach involves prediction and validating of targets via molecular modeling, western blotting and In Vivo MNU-induced mammary cancer. The PPI network showed the 573 edges between 214 nodes (targets) that are involved in breast cancer and important one are ESR-1, ESR-2, AR, EGFR, NOS3, MAPK, KDR, SRC and MET. Compound-target-pathway network involves 04 compounds and 221 interactive protein targets associated with breast cancer. GO and KEGG enrichment analysis predicted the ERR, c-MET, PDGFR-α/ß, EGFR, and VEGF as a key targets in the breast cancer treatment which are validated via molecular modeling. Expression of ER-α, AR and EGFR were significantly down regulated by AV in MCF-7 cell line. In addition, the immunoreactivity of ER-α was reduced significantly in MNU-induced mammary carcinoma, which is a key target in ER + breast cancer. Overall, this study scientifically light ups the pharmacological mechanism of AV in the treatment of breast cancer, strongly associated with the regulation of ESR signaling pathway.

Network analysis and molecular mapping for SARS-CoV-2 to reveal drug targets and repurposing of clinically developed drugs.

Novel coronavirus (SARS-CoV-2), turned out to be a global pandemic with unstoppable morbidity and mortality rate. However, till date there is no effective treatment found against SARS-CoV-2. We report on the major in-depth molecular and docking analysis by using antiretroviral (Lopinavir and ritonavir), antimalarial (Hydroxychloroquine), antibiotics (Azithromycin), and dietary supplements (Vitamin C and E) to provide new insight into drug repurposing molecular events involved in SARS-CoV-2. We constructed three drug-target-pathways-disease networks to predict the targets and drugs interactions as well as important pathways involved in SARS-CoV-2. The results suggested that by using the combination of Lopinavir, Ritonavir along with Hydroxychloroquine and Vitamin C may turned out to be the effective line of treatment for SARS-CoV-2 as it shows the involvement of PARP-1, MAPK-8, EGFR, PRKCB, PTGS-2, and BCL-2. Gene ontology biological process analysis further confirmed multiple viral infection-related processes (P < 0.001), including viral life cycle, modulation by virus, C-C chemokine receptor activity, and platelet activation. KEGG pathway analysis involves multiple pathways (P < 0.05), including FoxO, GnRH, ErbB, Neurotrophin, Toll-like receptor, IL-17, TNF, Insulin, HIF-1, JAK-STAT, Estrogen, NF-kappa, Chemokine, VEGF, and Thyroid hormone signaling pathway in SARS-CoV-2. Docking study was carried out to predict the molecular mechanism Thus, the potential drug combinations could reduce viral infectivity, viral replication, and abnormal host inflammatory responses and may be useful for multi-target drugs against SARS-CoV-2.

A network pharmacology-based approach to explore potential targets of Caesalpinia pulcherima: an updated prototype in drug discovery.

Caesalpinia pulcherima (CP) is a traditional herb used for the treatment of asthma, bronchitis, cancer, anti-bacterial, anti-fungal and as abortifacient. In the present study, bioactive components and potential targets in the treatment of breast cancer validated through in silico, in vitro and in vivo approach. The results for the analysis were as among 29 components, only four components were found active for further study which proved the use of CP as a multi-target herb for betterment of clinical uses. The results found by PPI states that our network has significant interactions which include the ESR-1, ESR-2, ESRRA, MET, VEGF, FGF, PI3K, PDK-1, MAPK, PLK-1, NEK-2, and GRK. Compound-target network involves 4 active compound and 150 target genes which elucidate the mechanisms of drug action in breast cancer treatment. Furthermore, on the basis of the above results the important proteins were fetched for the docking study which helps in predicting the possible interaction between components and targets. The results of the western blotting showed that CP regulates ER and EGFR expression in MCF-7 cell. In addition to this animal experimentation showed that CP significantly improved immunohistological status in MNU induced carcinoma rats. Network pharmacology approach not only helps us to confirm the study of the chosen target but also gave an idea of compound-target network as well as pathways associated to the CP for treating the complex metabolic condition as breast cancer and they importance for experimental verification.

Chemomodulatory effects of Alysicarpus vaginalis extract via mitochondria-dependent apoptosis and necroptosis in breast cancer.

The present study intended to assess the anticancer potential of Alysicarpus vaginalis ethyl acetate fraction (AVEAF) in breast cancer cell lines (MCF-7 and MDA-MB-453) and against N-methyl-N-nitrosourea (MNU) induced mammary carcinoma in Sprague-Dawley rats which resemble the human estrogen dependent breast cancer. The SRB assay showed that the maximum growth inhibition rate of AVEAF on MCF-7 cell was 27.12 at 100 µg/ml. Flow cytometry analysis observed that AVEAF induced the cell cycle arrest at the S phases and decreased in mitochondrial membrane potential on the MCF-7 cells. AVEAF elevated intracellular ROS level in the MCF-7 cells which were reversed with N-acetycysteine (2 mM) pretreatment indicating that AVEAF induced mitochondrial-mediated apoptosis via augmentation of intracellular ROS. Western blotting exhibited that AVEAF increased the expression of pro-apoptotic protein Bax while decreasing anti-apoptotic proteins Bcl-2 and Bcl-xL expression which promoted the cleavage of caspase-9, PARP1, RIPK 1, and RIPK 3. Additionally, AVEAF exerted anticancer effect on tumor-bearing rats and the tumor inhibition rate is 50%. Data of the study indicate that AVEAF exhibits In Vitro and In Vivo anticancer activities that associate with its ROS-mediated mitochondrial-mediated intrinsic pathway of apoptosis and necroptosis in MCF-7 cells and may serve as a potential against breast cancer.

Targeting Small Molecule Tyrosine Kinases by Polyphenols: New Move Towards Anti-tumor Drug Discovery.

BACKGROUND: Cancer is a complex disease involving genetic and epigenetic alteration that allows cells to escape normal homeostasis. Kinases play a crucial role in signaling pathways that regulate cell functions. Deregulation of kinases leads to a variety of pathological changes, activating cancer cell proliferation and metastases. The molecular mechanism of cancer is complex and the dysregulation of tyrosine kinases like Anaplastic Lymphoma Kinase (ALK), Bcr-Abl (Fusion gene found in patient with Chronic Myelogenous Leukemia (CML), JAK (Janus Activated Kinase), Src Family Kinases (SFKs), ALK (Anaplastic lymphoma Kinase), c-MET (Mesenchymal- Epithelial Transition), EGFR (Epidermal Growth Factor receptor), PDGFR (Platelet-Derived Growth Factor Receptor), RET (Rearranged during Transfection) and VEGFR (Vascular Endothelial Growth Factor Receptor) plays major role in the process of carcinogenesis. Recently, kinase inhibitors have overcome many problems of traditional cancer chemotherapy as they effectively separate out normal, non-cancer cells as well as rapidly multiplying cancer cells. METHODS: Electronic databases were searched to explore the small molecule tyrosine kinases by polyphenols with the help of docking study (Glide-7.6 program interfaced with Maestro-v11.3 of Schrödinger 2017) to show the binding energies of polyphenols inhibitor with different tyrosine kinases in order to differentiate between the targets. RESULTS: From the literature survey, it was observed that the number of polyphenols derived from natural sources alters the expression and signaling cascade of tyrosine kinase in various tumor models. Therefore, the development of polyphenols as a tyrosine kinase inhibitor against targeted proteins is regarded as an upcoming trend for chemoprevention. CONCLUSION: In this review, we have discussed the role of polyphenols as chemoreceptive which will help in future for the development and discovery of novel semisynthetic anticancer agents coupled with polyphenols.

Synthesis, Biological Investigation and Docking Study of Novel Chromen Derivatives as Anti-Cancer Agents.

BACKGROUND: According to the latest global cancer data, cancer burden rises to 18.1 million new cases and 9.6 million cancer deaths in 2018. Among that female breast cancer ranks as the fifth leading cause of death (627000 deaths, 6.6%). The main causative factor involved in breast cancer development and progression is the Estrogen Receptor (ER) which is the essential target for anti-cancer drug discovery. Since millennia ER-α has been considered as an oncology mark for the treatment of breast cancer. METHODS: A series of novel 6-methyl-3-(3-oxo-1-phenyl-3-(4-(2-(piperidin-1-yl)ethoxy)phenyl)propyl)-2Hchromen- 2-one was designed, synthesized and screened for their anti-breast cancer activity against estrogen receptor-positive MCF-7, ZR-75-1 and negative MDA-MB-435 human breast cancer cell lines. Estrogen level of all the potent cytotoxic compounds were measured on day 30 of intoxication was compared with the control and N-methyl-N-nitrosourea (MNU) group. The docking study was performed to predict binding orientation towards the estrogen receptor-α. RESULTS: Among the synthesized compounds C-3, C-5 and C-15 were showing potent cytotoxicity against estrogen receptor-positive MCF-7. The potent cytotoxic compounds C-3, C-5 and C-15 were further evaluated for in vivo anti-cancer activity by MNU induced mammary carcinoma in female sprague-dawley rats. The in vivo anticancer activity result shows that the compound C-5 has protuberant affinity towards estrogen receptor as standard TAM (Tamoxifen). The docking of the synthesized chromen derivatives showed interaction modes comparable to that of the co-crystallized ligands. CONCLUSION: The designed class has very promising starting point for the development and further improvement in anti-breast cancer class of drugs.