TGFβ Drives Metabolic Perturbations during Epithelial Mesenchymal Transition in Pancreatic Cancer: TGFβ Induced EMT in PDAC

TGF beta; Pancreatic cancer; Tumor microenvironmentTGF beta; Cancer de pancreas; Microambiente tumoralTGF beta; Càncer de pàncrees; Microambient tumoralPancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy wherein a majority of patients present metastatic disease at diagnosis. Although the role of epithelial to mesenchymal transition (EMT), mediated by transforming growth factor beta (TGFβ), in imparting an aggressive phenotype to PDAC is well documented, the underlying biochemical pathway perturbations driving this behaviour have not been elucidated. We used high-resolution mass spectrometry (HRMS) based molecular phenotyping approach in order to delineate metabolic changes concomitant to TGFβ-induced EMT in pancreatic cancer cells. Strikingly, we observed robust changes in amino acid and energy metabolism that may contribute to tumor invasion and metastasis. Somewhat unexpectedly, TGFβ treatment resulted in an increase in intracellular levels of retinoic acid (RA) that in turn resulted in increased levels of extracellular matrix (ECM) proteins including fibronectin (FN) and collagen (COL1). These findings were further validated in plasma samples obtained from patients with resectable pancreatic cancer. Taken together, these observations provide novel insights into small molecule dysregulation that triggers a molecular cascade resulting in increased EMT-like changes in pancreatic cancer cells, a paradigm that can be potentially targeted for better clinical outcomes.This study was supported by American Cancer Society (IRG-92-152-17 award number AWD4470404), Georgetown Lombardi Comprehensive Cancer Center Support Grant Developmental Funds and Ruesch Foundation to K.U. and A.K.C

Identifying inflammation-related targets of natural lactones using network pharmacology, molecular modeling and <i>in vitro</i> approaches

Natural lactones have been used in traditional and folklore medicine for centuries owing to their anti-inflammatory properties. The study uses a multifaceted approach to identify lead anti-inflammatory lactones from the SISTEMATX natural products database. The study analyzed the natural lactone database, revealing 18 lactones linked to inflammation targets. The primary targets were PTGES, PTGS1, COX-2, ALOX5 and IL1B. STX 12273 was the best hit, with the lowest binding energy and potential for inhibiting the COX-2 enzyme. The study suggested natural lactone, STX 12273, from the SISTEMATX database with anti-inflammatory potential and postulated its use for inflammation treatment or prevention. Communicated by Ramaswamy H. Sarma</p

Glycyrrhiza glabra extract and quercetin reverses cisplatin resistance in triple-negative MDA-MB-468 breast cancer cells via inhibition of cytochrome P450 1B1 enzyme

© 2017 Elsevier Ltd The development of multi-drug resistance to existing anticancer drugs is one of the major challenges in cancer treatment. The over-expression of cytochrome P450 1B1 enzyme has been reported to cause resistance to cisplatin. With an objective to discover cisplatin-resistance reversal agents, herein, we report the evaluation of Glycyrrhiza glabra (licorice) extracts and its twelve chemical constituents for inhibition of CYP1B1 (and CYP1A1) enzyme in Sacchrosomes and live human cells. The hydroalcoholic extract showed potent inhibition of CYP1B1 in both Sacchrosomes as well as in live cells with IC50 values of 21 and 16 µg/mL, respectively. Amongst the total of 12 constituents tested, quercetin and glabrol showed inhibition of CYP1B1 in live cell assay with IC50 values of 2.2 and 15 µM, respectively. Both these natural products were found to be selective inhibitors of CYP1B1, and does not inhibit CYP2 and CYP3 family of enzymes (IC50 > 20 µM). The hydroalcoholic extract of G. glabra and quercetin (4) showed complete reversal of cisplatin resistance in CYP1B1 overexpressing triple negative MDA-MB-468 breast cancer cells. The selective inhibition of CYP1B1 by quercetin and glabrol over CYP2 and CYP3 family of enzymes was studied by molecular modeling studies

<i>ortho</i>-Amidoalkylation of Phenols via Tandem One-Pot Approach Involving Oxazine Intermediate

A new and efficient method for <i>ortho</i>-amidoalkylation of phenols via Mannich-type condensation with formaldehyde and lactams using recyclable solid acid catalyst is described. This is the first report for <i>ortho</i>-amidoalkylation of phenols by lactams via Mannich-type condensation. LC-ESI-MS/MS based mechanistic study revealed that reaction proceeds through <i>o</i>-quinone methide (<i>o</i>-QM) and an oxazine intermediate via tandem Knoevenagel condensation, formal [4 + 2]-Diels–Alder cycloaddition and acid catalyzed oxazine ring-opening

Unveiling the healing properties of 2,3-dehydrosilychristin: a potential silymarin-derived flavonolignan from <i>Vitex negundo</i>

The compound 2,3-dehydrosilychristin, a flavonolignan linked to silychristin and silymarin, remains intriguing due to its challenging isolation from silymarin. While silymarin has been the exclusive source of flavonolignans – silybin, silychristin and silydianin − 2,3-dehydrosilychristin is reported in this study from Vitex negundo Linn. leaves. 2,3-Dehydrosilychristin (7) and 14 other compounds were isolated through focused extraction. Its subsequent pharmacological evaluation demonstrated potent antioxidant and in-vitro anti-inflammatory effects, notably inhibiting cytokines TNF-α, IL-6, IL-8 and VEGF. In in-vivo assessments, 2,3-dehydrosilychristin (7) revealed remarkable hepatoprotective potential by reducing liver enzyme levels AST and ALT. These findings expand the potential of 2,3-dehydrosilychristin and suggest bioprospecting Vitex species as alternate sources of bioactive flavonolignans.</p

Discovery and Preclinical Development of IIIM-290, an Orally Active Potent Cyclin-Dependent Kinase Inhibitor

Rohitukine (<b>1</b>), a chromone alkaloid isolated from Indian medicinal plant <i>Dysoxylum binectariferum</i>, has inspired the discovery of flavopiridol and riviciclib, both of which are bioavailable only via intravenous route. With the objective to address the oral bioavailability issue of this scaffold, four series of rohitukine derivatives were prepared and screened for Cdk inhibition and cellular antiproliferative activity. The 2,6-dichloro-styryl derivative IIIM-290 (<b>11d</b>) showed strong inhibition of Cdk-9/T1 (IC₅₀ 1.9 nM) kinase and Molt-4/MIAPaCa-2 cell growth (GI₅₀ < 1.0 μM) and was found to be highly selective for cancer cells over normal fibroblast cells. It inhibited the cell growth of MIAPaCa-2 cells via caspase-dependent apoptosis. It achieved 71% oral bioavailability with in vivo efficacy in pancreatic, colon, and leukemia xenografts at 50 mg/kg, po. It did not have CYP/efflux-pump liability, was not mutagenic/genotoxic or cardiotoxic, and was metabolically stable. The preclinical data presented herein indicates the potential of <b>11d</b> for advancement in clinical studies

Discovery and Preclinical Development of IIIM-290, an Orally Active Potent Cyclin-Dependent Kinase Inhibitor

Rohitukine (<b>1</b>), a chromone alkaloid isolated from Indian medicinal plant <i>Dysoxylum binectariferum</i>, has inspired the discovery of flavopiridol and riviciclib, both of which are bioavailable only via intravenous route. With the objective to address the oral bioavailability issue of this scaffold, four series of rohitukine derivatives were prepared and screened for Cdk inhibition and cellular antiproliferative activity. The 2,6-dichloro-styryl derivative IIIM-290 (<b>11d</b>) showed strong inhibition of Cdk-9/T1 (IC₅₀ 1.9 nM) kinase and Molt-4/MIAPaCa-2 cell growth (GI₅₀ < 1.0 μM) and was found to be highly selective for cancer cells over normal fibroblast cells. It inhibited the cell growth of MIAPaCa-2 cells via caspase-dependent apoptosis. It achieved 71% oral bioavailability with in vivo efficacy in pancreatic, colon, and leukemia xenografts at 50 mg/kg, po. It did not have CYP/efflux-pump liability, was not mutagenic/genotoxic or cardiotoxic, and was metabolically stable. The preclinical data presented herein indicates the potential of <b>11d</b> for advancement in clinical studies