Rituraj Konwar

Role of interleukin-10 in breast cancer

Cytokines are low molecular weight regulatory proteins or glycoprotein that modulates the intensity and duration of immune response by stimulating or inhibiting the activation, proliferation, and/or differentiation of target cells. Different cytokines are known to have diverse role in breast cancer initiation and progression. Interleukin-10 (IL-10), a pleiotropic anti-inflammatory cytokine, induces immunosuppression and assists in escape from tumor immune surveillance. Like several other cytokines, IL-10 also can exert dual proliferative and inhibitory effect on breast tumor cells indicating a complex role of IL-10 in breast cancer initiation and progression. In this review, we tried to put together a comprehensive current view on significance of IL-10 in promotion, inhibition, and importance as prognosticator in breast cancer based on in vitro, in vivo, and clinical evidences. For literature collection, we conducted PubMed search with keywords “IL-10” and “breast cancer”.

Ligand anchored dendrimers based nanoconstructs for effective targeting to cancer cells

Dendrimers are considered versatile carriers especially for the treatment of diseases like cancer, AIDS, malaria etc. Cancer is a worldwide threat particularly in developing countries. A breakthrough research in this regard is a prime requirement. In the present study, folic acid was conjugated to fifth generation polypropylene imine (PPI) dendrimers and characterized through IR, NMR ((13)C and (1)H), ESI mass spectroscopy as well as electron microscopic studies. Doxorubicin (DOX), an effective anticancer drug, was used in the present study to develop and explore the anticancer potential of the dendrimer based formulations. DOX was loaded (approximately 26 and 65%) to the PPI dendrimers as well as folate conjugated PPI (PPI-FA) dendrimers, respectively. These ligand conjugated dendrimers displayed very less (approximately 3 and 4%, respectively, for PPI-FA and PPI-FA-DOX) hemolysis. The developed formulation PPI-FA-DOX was stable enough. In vitro drug release of the formulation was found to be faster in the acidic media than at the higher pH. The prepared formulation displayed a higher cell uptake in MCF-7 cancer cell lines as evidenced by fluorescence studies. The results suggested that, in future, folic acid conjugated PPI dendrimers may emerge as a better choice for anticancer drug targeting.

Vitamin D receptor (FokI, BsmI and TaqI) gene polymorphisms and type 2 diabetes mellitus: a North Indian study.

BACKGROUND The vitamin D receptor (VDR) gene is a candidate gene for susceptibility to several diseases. Studies on association between VDR polymorphisms and risk of type 2 diabetes (T2DM) in different ethnic populations are yet inconclusive. AIMS This study was conducted to evaluate association between VDR polymorphisms and genetic susceptibility to T2DM in the north Indian population. SETTINGS AND DESIGN One hundred clinically diagnosed T2DM patients and 160 healthy controls from the north Indian population were recruited for genetic association study. MATERIALS AND METHODS Genomic DNA was extracted from blood and genotyped for the single nucleotide polymorphism SNPs of FokI (T/C) [rs2228570], BsmI (A/G) [rs1544410] and TaqI (C/T) [rs731236] by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) analysis. STATISTICAL ANALYSIS USED Genotype distribution and allelic frequencies were compared between patients and controls. Mean values and odds ratios (ORs) with 95% confidence interval (CI) were calculated using SPSS software (version 15.0). RESULTS The genotype distribution, allele and haplotype frequencies of VDR polymorphism did not differ significantly between patients and controls. Mean age and waist-hip ratio of patients were found to be associated with VDR polymorphism. Combination studies showed FFBbtt increased the risk of T2DM in north Indians. CONCLUSIONS Our data suggest that VDR gene polymorphism in combination of genotypes is associated with the risk of T2DM and thus requires further studies as a probable genetic risk marker for T2DM.

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.

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.

Diversity oriented synthesis of pyran based polyfunctional stereogenic macrocyles and their conformational studies.

A new approach to synthesize a homologous series of 14-, 15-, and 16-membered drug-like, macrocyclic glycoconjugates involving TBAHS promoted azide-propenone intramolecular cycloaddition in designed C-glycopyranosyl butenones from a simple sugar d-glucose and d-mannose is reported.

Anti-tumor activity of a new series of benzoxazepine derivatives in breast cancer

A series of new benzoxazepine derivatives substituted with different alkoxy and aryloxy group were synthesized comprising synthetic steps of Mitsunobu reaction, lithium aluminum hydride (LAH) reduction, followed by debenzylation and finally intramolecular Mitsunobu cyclization. The new benzoxazepines specifically inhibited growth of breast cancer cell lines, MCF-7 and MDA-MB-231, but lack cytotoxicity to normal HEK-293 cells. The cell growth inhibition induced by the active compounds was due to cell cycle arrest at G(0)/G(1) phase. The active compound could cause significant reduction in tumor volume of MCF-7 xenograft tumor in nude mice model and their activity was comparable to that of tamoxifen citrate at 16mgkg(-1) dose at 30days of treatment. The identified most active compounds of the series have specific advantages as anti-cancer agent in breast cancer than tamoxifen.

Synthesis and biological evaluation of 3,4,6-triaryl-2-pyranones as a potential new class of anti-breast cancer agents.

A series of 3,4,6-triaryl-2-pyranones, new class of anti-breast cancer agents, have been synthesized as a structural variants of cyclic triphenylethylenes by replacing the fused benzene ring with pendant phenyl ring to mimic the phenolic A ring of estradiol. Nine of these newly synthesized pyranones exhibited significant anti-proliferative activity in both ER+ve and ER-ve breast cancer cell lines. Four active non-cytotoxic compounds 5c, 5d, 5g and 5h showed specific and selective cytotoxicity and two compounds 5d and 5h induced significant DNA fragmentation in both MCF-7 and MDA-MB-231 cell lines. Based on RBA studies, the molecules probably act in an ER-independent mechanism. The involved pathway was observed as caspase-dependant apoptosis in MCF-7 cells. However, the particular caspases involved and the possible cellular target through which this series of compounds mediate cell death are not known.

Reinventing the ACE inhibitors: some old and new implications of ACE inhibition

Since their inception, angiotensin-converting enzyme (ACE) inhibitors have been used as first-line therapy for the treatment of cardiovascular and renal diseases. They restore the balance between the vasoconstrictive salt-retentive and hypertrophy-causing peptide angiotensin II (Ang II) and bradykinin, a vasodilatory and natriuretic peptide. As ACE is a promiscuous enzyme, ACE inhibitors alter the metabolism of a number of other vasoactive substances. ACE inhibitors decrease systemic vascular resistance without increasing heart rate and promote natriuresis. They have been proven effective in the treatment of hypertension, and reduce mortality in congestive heart failure and left ventricular dysfunction after myocardial infarction. They inhibit ischemic events and stabilize plaques. Furthermore, they delay the progression of diabetic nephropathy and neuropathy and act as antioxidants. Ongoing studies have elucidated protective roles for them in both memory-related disorders and cancer. Lastly, N- and C-domain selective ACE inhibitors have led to new uses for ACE inhibitors.

Neo-tanshinlactone inspired synthesis, in vitro evaluation of novel substituted benzocoumarin derivatives as potent anti-breast cancer agents.

A small library of novel benzocoumarin derivatives based on naturally occurring neo-tanshinlactone scaffold was constructed and their antiproliferative activities against breast cancer cells MCF-7 and MDA-MB-231 were evaluated. A number of derivatives showed good anti-breast cancer activity, in some cases higher to that of the reference compound tamoxifen. In particular, benzocoumarins Bc-5, Bc-8 and Bc-9 strongly inhibited the proliferation of MCF-7 cancer cell line with the IC(50) values of 3.8, 7.9 and 6.5 μM, respectively. The compounds were capable of inducing nuclear fragmentation, cell cycle arrest and caspase dependent apoptosis in MCF-7 cell lines. In addition, these derivatives were devoid of cytotoxic effect against normal osteoblast cells. These synthetic benzocoumarins hold promises for developing safer alternative to the existing anti-breast cancer agents.