Asif Khurshid Qazi

Interaction of natural products with cell survival and signaling pathways in the biochemical elucidation of drug targets in cancer

The use of natural products with therapeutic properties is as ancient as human civilization and for a long time mineral, plant and animal products were the main sources of drugs. Worldwide sales of medicinal plants, crude extracts and finished products amounted to US

One-pot synthesis and cytotoxic evaluation of amide-linked 1,4-disubstituted 1,2,3-bistriazoles

15 billion in 1999 and it increased to

Synthesis, antimicrobial and cytotoxicity study of 1,3-disubstituted-1H-naphtho[1,2-e][1,3]oxazines

23 billion in 2002. More interestingly, the influence of natural products upon anticancer drug discovery and design cannot be underestimated. Approximately 60% of all drugs in clinical trials are either a natural product, compounds derived from natural products or contain pharmacophores derived from active natural products. Thus, even today, in the presence of massive numbers of agents from combinatorial libraries, compounds from natural sources are still in the forefront of cancer chemotherapeutics as sources of active drug types, as well as being involved in drug discovery in diseases such as microbial and parasitic infections and the control of cholesterol/lipids, among other functions.

Recent Development in Targeting PI3K-Akt-mTOR Signaling for Anticancer Therapeutic Strategies

A series of amide-linked 1,4-disubstituted 1,2,3-bistriazoles have been synthesized employing copper(I)-catalyzed azide–alkyne cycloaddition reaction. All the newly synthesized compounds were screened for in vitro cytotoxicity against a panel of five human cancer cell lines; Fibrosarcoma (HT-1080), Colon (colo205, HCT-116), and Lung (A549, NCIH322). Some of the bistriazoles exhibited moderate to good activity. Compounds 3n and 3o were found to be the more active and displayed broad spectrum activity against all the cancer cell lines under investigation. Further, to study the binding modes for the two more potent compounds 3n and 3o against Human topoisomerase II, docking simulations have been carried out.

Understanding Histone Deacetylases in the Cancer Development and Treatment: An Epigenetic Perspective of Cancer Chemotherapy

A series of new 1,3-disubstituted-1H-naphtho[1,2-e][1,3]oxazines (3 and 7) was synthesized in good yields and the structure was determined with the help of NMR, 2D-NMR, HRMS studies and X-ray crystallography. These compounds were tested in vitro for their antibacterial activity against Gram-positive and Gram-negative bacteria and as well as for antifungal activity. The compounds 3c, 3e, 7a, 7d and 7k showed significant antibacterial activity and 7l showed moderate antifungal activity. The cytotoxicity of 1,3-disubstituted-1H-naphtho[1,2-e][1,3]oxazines showed that 3e and 7e are more effective against breast, lung and colon cell proliferation.

Isolation and antiproliferative activity of Lotus corniculatus lectin towards human tumour cell lines.

Cancer is a diverse class of diseases which differ widely in their cause and biology. The aberrant behavior of cancer reflects up regulation of certain oncogenic signaling pathways that promote proliferation, inhibit apoptosis, and enable the cancer to spread and evoke angiogenesis. Phosphoinositide-3-kinase(PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway controls various biological processes that are important for normal functioning of the cell via cell cycle progression, survival, migration, transcription, translation and metabolism. However, PI3K signaling pathway is dysregulated almost in all cancers which is due to the amplification and genetic mutation of PI3K gene, encoding catalytic and regulatory subunit of PI3K isoforms. The current review focuses on the structural features of various PI3K isoforms including Akt and mTOR and their inhibition using specific small molecule inhibitors in an attempt to achieve an attractive target for cancer prevention and chemotherapy.

Therapeutic Targeting of Cancer Cell Metabolism: Role of Metabolic Enzymes, Oncogenes and Tumor Suppressor Genes

Cancer is a pathologic condition that involves genetic and epigenetic events culminating in neoplastic transformation. Alteration in epigenetic events that regulate the transcriptional activity of genes associated with various signaling pathways can influence multiple stages of tumorigenesis. In cancer cells, an imbalance often exists between histone acetyl transferase and histone deacetylase (HDAC) activities, and current research focuses actively on seeking competitive HDAC inhibitors (HDACi) for chemotherapeutic intervention. HDACi are proving useful for cancer prevention and therapy by virtue of their ability to reactivate the expression of epigenetically silenced genes, including those involved in differentiation, cell cycle regulation, apoptosis, angiogenesis, invasion, and metastasis. Furthermore, epidemiological studies suggest that different diets such as intake of cruciferous vegetables may lower the risk of different cancers, and there is growing interest in identifying the specific chemoprotective constituents and mechanistic insights of their action. Interestingly, it has been observed that cancer cells are more sensitive than nontransformed cells to apoptotic induction by some HDACi. Although the mechanistic basis for this sensitivity is unclear, yet HDACi have emerged as important epigenetic target for single and combinatorial chemotherapy. HDACi derived from diverse sources such as microbial, dietary, and synthetic increase acetylation level of cells and bring about anti-proliferative and apoptotic effects specific to cancer cells by way of their role in cell cycle regulation and expression of epigenetically silenced genes.

Quinazoline based small molecule exerts potent tumour suppressive properties by inhibiting PI3K/Akt/FoxO3a signalling in experimental colon cancer

The objective of the study was to investigate the anti cancer activity of a lectin isolated from Lotus corniculatus seeds. A tetrameric 70kDa galactose specific lectin was purified using two step simple purification protocol which involved affinity chromatography on AF-BlueHC650M and gel filtration on Sephadex G-100. The lectin was adsorbed on AF-BlueHC650M and desorbed using 1M NaCl in the starting buffer. Gel filtration on Sephadex G-100 yielded a major peak absorbance that gave two bands of 15kDa and 20kDa in SDS PAGE. Hemagglutination activity was completely preserved, when the temperature was in the range of 20-60°C. However, drastic reduction in activity occurred at temperatures above 60°C. Full hemagglutination activity was retained at ambient pH 4-12. Thereafter no activity was observed above pH 13. Hemaglutination of the lectin was inhibited by d-galactose. The lectin showed a strong antiproliferative activity towards human leukemic (THP-1) cancer cells followed by lung cancer (HOP62) cells and HCT116 with an IC50 of 39μg/ml and 50μg/ml and 60μg/ml respectively. Flow cytometry analysis showed an increase in the percentage of cells in sub G0G1 phase confirming that Lotus corniculatus lectin induced apoptosis. Morphological observations showed that Lotus corniculatus lectin (LCL) treated THP-1 cells displayed apparent apoptosis characteristics such as nuclear fragmentation, appearance of membrane enclosed apoptotic bodies and DNA fragmentation. Lotus corniculatus lectin (LCL) effectively inhibits the cell migration in a dose dependent manner as indicated by the wound healing assay.

Antiproliferative Activity of Lavatera cashmeriana- Protease Inhibitors towards Human Cancer Cells

Cancer cells compared to their normal counterparts reveal different metabolic needs and this differential requirement of metabolic intermediates and their subsequent consequences require an elaborate understanding of cancer cell metabolism and increased energy production in these cells. Nevertheless these metabolic differences have provided opportunities for developing novel therapeutic approaches for the cancer diagnosis and treatment. In addition enhanced proliferative capacities of tumor cells associated with aberrations of many signal transduction pathways resulting from genetic or epigenetic alterations has made it possible to develop countless targeted therapeutics for several types of malignancies. However at present most of our understanding about the dysregulated cancer cell metabolism is at physiological stages. With advancement in technology development, we may eventually be able to differentiate the metabolic differences between normal cells and cancerous at the single-tumor level that may influence the development of personalized cancer medicine. In this review, the focal point will be the recent developments in understanding the crucial role of metabolic enzymes, oncogenes and tumor suppressor genes in progression of cancer and their targeting to establish the most appropriate therapeutic strategies for better clinical outcome.

Modulation of glycolysis and lipogenesis by novel PI3K selective molecule represses tumor angiogenesis and decreases colorectal cancer growth.

Deregulation of PI3K signalling pathway is strongly involved in pathology of cancer and development of resistance in tumour cells. Here, we report that pharmacologically active vasicinone analogue, RLX (7, 8, 9, 10-Tetrahydroazepino [2, 1-b] quinazolin-12-(6H)-on), exhibited potent anticancer activities both in vitro and in vivo. In this study, RLX treatment displayed strong inhibition of proliferation against various cancer cell lines. However, colon cancer cells were found to be the most sensitive towards RLX mediated inhibition of proliferation. The result showed that RLX treatment followed strong concentration dependent inhibition of HCT-116 cell proliferation and colony formation. RLX treatment to HCT-116 was observed to be associated with down-regulation of p110α and p85 subunits of PI3K thereby decreasing the expression of subsequent downstream effector proteins. Interestingly, silencing of PI3K gene by siRNA in combination with RLX confirmed the anti-proliferation effect of RLX against HCT-116 cells and is mediated by the PI3K pathway. We also found that RLX induced sub-G1 arrest and mitochondrial potential loss followed by pFoxO3a(Thr32) nuclear-cytoplasmic translocation inhibition. Moreover, RLX treatment in in vivo models substantially resulted in a tumour growth inhibition. Overall, our findings reveal the functional role of the PI3K/Akt/FoxO3a pathway that gets deregulated in cancer and suggests its simultaneous targeting by RLX thereby further identifying the compound as a potent inhibitor of the PI3K/Akt/FoxO3a pathway under in vitro and tumour regression in vivo.