Jayanta Sarkar

Synthesis and in vitro evaluation of novel coumarin-chalcone hybrids as potential anticancer agents.

A series of coumarin-chalcone hybrids have been synthesized and evaluated for their in vitro cytotoxicity against a panel of four human cancer cell lines and normal fibroblasts (NIH3T3). Among 21 compounds screened, three compounds (23, 25 and 26) showed IC(50) range from 3.59 to 8.12 μM. The most promising compound 26 showed around 30-fold more selectivity towards C33A (cervical carcinoma) cells over normal fibroblast NIH3T3 cells with an IC(50) value of 3.59 μM.

Oral cancer: risk factors and molecular pathogenesis.

IntroductionOral cancer is one of the most common cancers and it constitutes a major health problem particularly in developing countries. It is one of the leading causes of death. Tobacco and alcohol consumption appears to be the major determinants of oral cancer.Materials and methodsThe literature search was carried out in NCBI Pubmed database using keywords “oral cancer”, “risk factor”, “epidemiology” and “patho*”. Some basic information was also obtained from textbook and medical university websites.ResultsSeveral risk factors have been well characterized to be associated with oral cancer with substantial evidences. The development of oral cancer is a multistep process involving the accumulation of genetic and epigenetic alterations in key regulatory genes. Experimental pathological studies of oral cancer in animal models and direct molecular genetic analysis of oral cancer subjects in recent times have revealed a substantial amount of knowledge on specific gene alterations or other genetic mechanisms involved in initiation and subsequent progression.ConclusionConsidering known risk factors, oral cancer appears to be to a certain extent, a preventable disease. Recent development of molecular picture of pathoprogression and molecular genetic tools opens the avenue for easier diagnosis, better prognostication and efficient therapeutic management.

Synthesis and cytotoxicity evaluation of (tetrahydro-β-carboline)-1,3,5-triazine hybrids as anticancer agents

A series of tetrahydro-beta-carbolines and 1,3,5-triazine hybrids have been synthesized and evaluated for their cytotoxicity against a panel of eight human cancer cell lines and normal human fibroblasts (NIH3T3). It led us to discovery of racemic compounds 69, 71 and 75, which are selectively cytotoxic towards KB (oral cancer) cell line with IC50 values of 105.8, 664.7 and 122.2 nM, respectively; while their enantiopure forms are less active and not selective. Enantiopure compound 42 showed 2.5 times more selectivity towards MCF7 cells over normal fibroblast NIH3T3 cells with an IC50 value of 740 nM, also arrests cell cycle in G1 phase and induces apoptosis in MCF7 and MDA MB231 cell lines.

Cassane Diterpenes from Caesalpinia bonduc.

Three cassane diterpene hemiketals, caesalpinolide-C, caesalpinolide-D, caesalpinolide-E and one cassane furanoditerpene were isolated from Caesalpinia bonduc. The molecular structures were elucidated using NMR spectroscopy in combination with IR, UV and mass spectral data and relative stereochemistries were determined through ROESY correlation. The isolated compounds were tested for their antiproliferative activity against MCF-7 (breast adenocarcinoma), DU145 (prostate carcinoma), C33A (Cervical carcinoma) and Vero (African green monkey kidney fibroblast) cells.

Antiproliferative action of Xylopia aethiopica fruit extract on human cervical cancer cells.

The anticancer potential of Xylopia aethiopica fruit extract (XAFE), and the mechanism of cell death it elicits, was investigated in various cell lines. Treatment with XAFE led to a dose‐dependent growth inhibition in most cell lines, with selective cytotoxicity towards cancer cells and particularly the human cervical cancer cell line C‐33A. In this study, apoptosis was confirmed by nuclear fragmentation and sub‐G0/G1 phase accumulation. The cell cycle was arrested at the G2/M phase with a decreased G0/G1 population. A semi‐quantitative gene expression study revealed dose‐dependent up‐regulation of p53 and p21 genes, and an increase in the Bax/Bcl‐2 ratio. These results indicate that XAFE could be a potential therapeutic agent against cancer since it inhibits cell proliferation, and induces apoptosis and cell cycle arrest in C‐33A cells. Copyright

Natural antitubulin agents: Importance of 3,4,5-trimethoxyphenyl fragment

Microtubules are polar cytoskeletal filaments assembled from head-to-tail and comprised of lateral associations of α/β-tubulin heterodimers that play key role in various cellular processes. Because of their vital role in mitosis and various other cellular processes, microtubules have been attractive targets for several disease conditions and especially for cancer. Antitubulin is the most successful class of antimitotic agents in cancer chemotherapeutics. The target recognition of antimitotic agents as a ligand is not much explored so far. However, 3,4,5-trimethoxyphenyl fragment has been much highlighted and discussed in such type of interactions. In this review, some of the most important naturally occurring antimitotic agents and their interactions with microtubules are discussed with a special emphasis on the role of 3,4,5-trimethoxyphenyl unit. At last, some emerging naturally occurring antimitotic agents have also been tabulated.

α-Solanine induces ROS-mediated autophagy through activation of endoplasmic reticulum stress and inhibition of Akt/mTOR pathway

α-Solanine is a glycoalkaloid found in species of the nightshade family including potato. It was primarily reported to have toxic effects in humans. However, there is a growing body of literature demonstrating in vitro and in vivo anticancer activity of α-solanine. Most of these studies have shown activation of apoptosis as the underlying mechanism in antitumor activity of α-solanine. In this study, we report α-solanine as a potential inducer of autophagy, which may act synergistically or in parallel with apoptosis to exert its cytotoxic effect. Induction of autophagy was demonstrated by several assays including electron microscopy, immunoblotting of autophagy markers and immunofluorescence for LC3 (microtubule-associated protein 1 (MAP1) light chain-3) puncta. α-Solanine-induced autophagic flux was demonstrated by additionally enhanced – turnover of LC3-II and – accumulation of LC3-specific puncta after co-incubation of cells with either of the autophagolysosome inhibitors – chloroquine and – bafilomycin A1. We also demonstrated α-solanine-induced oxidative damage in regulating autophagy where pre-incubation of cells with reactive oxygen species (ROS) scavenger resulted in suppression of CM-H2DCFDA (5 (and 6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate acetyl ester) fluorescence as well as decrease in LC3-II turnover. α-Solanine treatment caused an increase in the expression of endoplasmic reticulum (ER) stress proteins (BiP, activating transcription factor 6 (ATF6), X-box-binding protein 1, PERK, inositol-requiring transmembrane kinase/endonuclease 1, ATF4 and CCAAT-enhancer-binding protein (C/EBP)-homologous protein) suggesting activation of unfolded protein response pathway. Moreover, we found downregulation of phosphorylated Akt (Thr308 and Ser473), mammalian target of rapamycin (mTOR; Ser2448 and Ser2481) and 4E-BP1 (Thr37/46) by α-solanine implying suppression of the Akt/mTOR pathway. Collectively, our results signify that α-solanine induces autophagy to exert anti-proliferative activity by triggering ER stress and inhibiting Akt/mTOR signaling pathway.

Anti-tumour activity of a novel coumarin–chalcone hybrid is mediated through intrinsic apoptotic pathway by inducing PUMA and altering Bax/Bcl-2 ratio

Coumarins and chalcones are secondary plant metabolites which have shown an array of pharmacological properties including anti-tumour activity. We have previously reported on the synthesis and anti-proliferative activity of a series of novel coumarin–chalcone hybrids. Now we report on the in vivo efficacy as well as mechanism of action of the most potent molecule of the series, S009-131. Oral administration of this molecule resulted in regression of tumours induced by HeLa cell xenografts in nod SCID mice. The molecule inhibited proliferation of cervical cancer cells (HeLa and C33A) by inducing apoptosis and arresting cell cycle at G2/M phase. Apoptosis was induced through induction of caspase-dependent intrinsic pathway and alterations in the cellular levels of Bcl-2 family proteins. The mitochondrial transmembrane potential got highly depleted in S009-131 treated cells due to an increase in Bax/Bcl-2 ratio and intracellular ROS. The molecule induced release of cytochrome c into the cytosol and activation of initiator caspase-9 and executioner caspases-3/7. Tumour suppressor protein p53 and its transcriptional target PUMA were up regulated, suggesting their role in mediating the cell death. These results suggest that S009-131 is a potent candidate for the chemotherapy of cervical carcinoma.

Mixed infection of peste des petits ruminants and orf on a goat farm in Shahjahanpur, India

191 bp 200 bp N M P 1 2 3 4 5 FIG 1: Agarose gel electrophoresis of peste des petits ruminants virus (PPRV) DNA amplified by M genereverse transcriptasePCR. Lane N Healthy goat splenic tissue (negative control), Lane M 100 base pair DNA ladder marker, Lane P PRRV Sungri/ 96-vaccine virusinfected Vero (positive control), Lane 1 Blood sample from a goat with clinical signs characteristic of PPRV infection, Lane 2 Lung tissue, Lane 3 Caecum tissue, Lane 4 Splenic tissue, Lane 5 Nasal swab from a goat with nasal discharge

Synthesis of novel β-carboline based chalcones with high cytotoxic activity against breast cancer cells.

A series of novel β-carboline based chalcones was synthesized and evaluated for their cytotoxic activity against a panel of human cancer cell lines. Among them we found that two of the compounds 7c and 7d, showed marked anti-proliferative activity in a panel of solid tumor cell lines with highest effect in breast cancer. The compounds 7c and 7d showed an IC50 of 2.25 and 3.29 μM, respectively against human breast cancer MCF-7 cell line. Further, the compound 7c markedly induced DNA fragmentation and apoptosis in breast cancer cells.