Ravi Thakur

Bio: Ravi Thakur is an academic researcher from Central Drug Research Institute. The author has contributed to research in topics: Controlled release & Cancer stem cell. The author has an hindex of 11, co-authored 17 publications receiving 585 citations. Previous affiliations of Ravi Thakur include Council of Scientific and Industrial Research & Eppley Institute for Research in Cancer and Allied Diseases.

Inhibition of STAT3, FAK and Src mediated signaling reduces cancer stem cell load, tumorigenic potential and metastasis in breast cancer

Abstract: Cancer stem cells (CSCs) are responsible for aggressive tumor growth, metastasis and therapy resistance. In this study, we evaluated the effects of Shikonin (Shk) on breast cancer and found its anti-CSC potential. Shk treatment decreased the expression of various epithelial to mesenchymal transition (EMT) and CSC associated markers. Kinase profiling array and western blot analysis indicated that Shk inhibits STAT3, FAK and Src activation. Inhibition of these signaling proteins using standard inhibitors revealed that STAT3 inhibition affected CSCs properties more significantly than FAK or Src inhibition. We observed a significant decrease in cell migration upon FAK and Src inhibition and decrease in invasion upon inhibition of STAT3, FAK and Src. Combined inhibition of STAT3 with Src or FAK reduced the mammosphere formation, migration and invasion more significantly than the individual inhibitions. These observations indicated that the anti-breast cancer properties of Shk are due to its potential to inhibit multiple signaling proteins. Shk also reduced the activation and expression of STAT3, FAK and Src in vivo and reduced tumorigenicity, growth and metastasis of 4T1 cells. Collectively, this study underscores the translational relevance of using a single inhibitor (Shk) for compromising multiple tumor-associated signaling pathways to check cancer metastasis and stem cell load.

Pharmacological modulation of beta-catenin and its applications in cancer therapy

Abstract: Beta-catenin (β-catenin) is a multifunction protein with a central role in physiological homeostasis. Its abnormal expression leads to various diseases including cancer. In normal physiology, β-catenin either maintains integrity of epithelial tissues or controls transcription of various genes on extracellular instigations. In epithelial tissues, β-catenin functions as a component of the cadherin protein complex and regulates epithelial cell growth and intracellular adhesion. In Wnt signalling, β-catenin is a major transcriptional modulator and plays a crucial role in embryogenesis, stem cell renewal and organ regeneration. Aberrant expression of β-catenin can induce malignant pathways in normal cells and its abnormal activity is also exploited by existing malignant programmes. It acts as an oncogene and modulates transcription of genes to drive cancer initiation, progression, survival and relapse. Abnormal expression and function of β-catenin in cancer makes it a putative drug target. In the past decade, various attempts have been made to identify and characterize various pharmacological inhibitors of β-catenin. Many of these inhibitors are currently being investigated for their anticancer activities in a variety of cancers. The first half of this review will focus on the role of β-catenin in cancer initiation, maintenance, progression and relapse whereas the second half will briefly summarize the recent progress in development of agents for the pharmacological modulation of β-catenin activity in cancer therapeutics.

A novel therapeutic approach with Caviunin-based isoflavonoid that en routes bone marrow cells to bone formation via BMP2/Wnt-β-catenin signaling.

Abstract: Recently, we reported that extract of Dalbergia sissoo made from leaves and pods have antiresorptive and bone-forming effects. The positive skeletal effect attributed because of active molecules present in the extract of Dalbergia sissoo. Caviunin 7-O-[β-D-apiofuranosyl-(1-6)-β-D-glucopyranoside] (CAFG), a novel isoflavonoid show higher percentage present in the extract. Here, we show the osteogenic potential of CAFG as an alternative for anabolic therapy for the treatment of osteoporosis by stimulating bone morphogenetic protein 2 (BMP2) and Wnt/β-catenin mechanism. CAFG supplementation improved trabecular micro-architecture of the long bones, increased biomechanical strength parameters of the vertebra and femur and decreased bone turnover markers better than genistein. Oral administration of CAFG to osteopenic ovariectomized mice increased osteoprogenitor cells in the bone marrow and increased the expression of osteogenic genes in femur and show new bone formation without uterine hyperplasia. CAFG increased mRNA expression of osteoprotegerin in bone and inhibited osteoclast activation by inhibiting the expression of skeletal osteoclastogenic genes. CAFG is also an effective accelerant for chondrogenesis and has stimulatory effect on the repair of cortical bone after drill-hole injury at the tissue, cell and gene level in mouse femur. At cellular levels, CAFG stimulated osteoblast proliferation, survival and differentiation. Signal transduction inhibitors in osteoblast demonstrated involvement of p-38 mitogen-activated protein kinase pathway stimulated by BMP2 to initiate Wnt/β-catenin signaling to reduce phosphorylation of GSK3-β and subsequent nuclear accumulation of β-catenin. Osteogenic effects were abrogated by Dkk1, Wnt-receptor blocker and FH535, inhibitor of TCF-complex by reduction in β-catenin levels. CAFG modulated MSC responsiveness to BMP2, which promoted osteoblast differentiation via Wnt/β-catenin mechanism. CAFG at 1 mg/kg(/)day dose in ovariectomy mice (human dose ∼0.081 mg/kg) led to enhanced bone formation, reduced bone resorption and bone turnover better than well-known phytoestrogen genistein. Owing to CAFG's inherent properties for bone, it could be positioned as a potential drug, food supplement, for postmenopausal osteoporosis and fracture repair.

Controlled drug delivery vehicles for cancer treatment and their performance.

Abstract: Although conventional chemotherapy has been successful to some extent, the main drawbacks of chemotherapy are its poor bioavailability, high-dose requirements, adverse side effects, low therapeutic indices, development of multiple drug resistance, and non-specific targeting. The main aim in the development of drug delivery vehicles is to successfully address these delivery-related problems and carry drugs to the desired sites of therapeutic action while reducing adverse side effects. In this review, we will discuss the different types of materials used as delivery vehicles for chemotherapeutic agents and their structural characteristics that improve the therapeutic efficacy of their drugs and will describe recent scientific advances in the area of chemotherapy, emphasizing challenges in cancer treatments.

Suppression of ICE and Apoptosis in Mammary Epithelial Cells by Extracellular Matrix

Abstract: Suppression of ICE and Apoptosis in Mammary Epithelial Cells by Extracellular Matrix Nancy Boudreau,* Carolyn J. Sympson, Zena Werb, Mina J. Bissell N. Boudreau and M. J. Bissell Life Sciences Division, Lawrence Berkeley Laboratory 1 Cyclotron Road, Building 83, Berkeley, CA 94720, USA. C. J. Sympson Life Sciences Division, Lawrence Berkeley Laboratory 1 Cyclotron Road, Building 83, Berkeley, CA 94720, USA Laboratory of Radiobiology and Environmental Health University of California, San Francisco, CA 94143, USA. Z. Werb Laboratory of Radiobiology and Environmental Health University of California, San Francisco, CA 94143, USA. *To whom correspondence should be addressed. LBNL/DOE funding & contract number: DE-AC02-05CH11231 DISCLAIMER This document was prepared as an account of work sponsored by the United States Government. While this document is believed to contain correct information, neither the United States Government nor any agency thereof, nor The Regents of the University of California, nor any of their employees, makes any warranty, express or implied, or assumes any legal responsibility for the accuracy, completeness, or usefulness of any information, apparatus, product, or process disclosed, or represents that its use would not infringe privately owned rights. Reference herein to any specific commercial product, process, or service by its trade name, trademark, manufacturer, or otherwise, does not necessarily constitute or imply its endorsement, recommendation, or favoring by the United States Government or any agency thereof, or The Regents of the University of California. The views and opinions of authors expressed herein do not necessarily state or reflect those of the United States Government or any agency thereof or The Regents of the University of California.

Fate decision of mesenchymal stem cells: adipocytes or osteoblasts?

Abstract: Mesenchymal stem cells (MSCs), a non-hematopoietic stem cell population first discovered in bone marrow, are multipotent cells capable of differentiating into mature cells of several mesenchymal tissues, such as fat and bone. As common progenitor cells of adipocytes and osteoblasts, MSCs are delicately balanced for their differentiation commitment. Numerous in vitro investigations have demonstrated that fat-induction factors inhibit osteogenesis, and, conversely, bone-induction factors hinder adipogenesis. In fact, a variety of external cues contribute to the delicate balance of adipo-osteogenic differentiation of MSCs, including chemical, physical, and biological factors. These factors trigger different signaling pathways and activate various transcription factors that guide MSCs to commit to either lineage. The dysregulation of the adipo-osteogenic balance has been linked to several pathophysiologic processes, such as aging, obesity, osteopenia, osteopetrosis, and osteoporosis. Thus, the regulation of MSC differentiation has increasingly attracted great attention in recent years. Here, we review external factors and their signaling processes dictating the reciprocal regulation between adipocytes and osteoblasts during MSC differentiation and the ultimate control of the adipo-osteogenic balance.

The biological activities, chemical stability, metabolism and delivery systems of quercetin: A review

Abstract: Background Quercetin, one of the most well-known flavonoids, has been included in human diet for a long history. The use of quercetin has been widely associated with a great number of health benefits, including antioxidant, anti-inflammatory, antiviral and anticancer as well as the function to ease some cardiovascular diseases (i.e., heart disease, hypertension, and high blood cholesterol). However, poor water solubility, chemical instability and low bioavailability of quercetin greatly limit its applications. Utilization of delivery systems can improve its stability, efficacy and bioavailability. Scope and approach In this review, biological activities, chemical stability, metabolism and toxicity of quercetin and different delivery systems for quercetin were discussed. Key findings and conclusions Quercetin digested in human body (e.g., mouth, small intestine, liver, kidneys) undergoes glucuronidation, sulfation or methylation. During the food processing and storage, many factors such as heat, pH, metal ions, could affect the chemical stability (including oxidation and degradation) of quercetin. Utilization of delivery systems including lipid-based carriers, nanoparticles, inclusion complexes, micelles and conjugates-based encapsulation has the potential to improve both the stability and bioavailability and thus health benefits of quercetin. Each delivery system has its unique advantages and shortcomings, and the specific selection should be based on the application domains. Moreover, the exploration of natural food-grade ingredients as main compositions of delivery systems for quercetin might be required in the future.

The extracellular matrix in tumor progression and metastasis.

Abstract: The extracellular matrix (ECM) constitutes the scaffold of tissues and organs. It is a complex network of extracellular proteins, proteoglycans and glycoproteins, which form supramolecular aggregates, such as fibrils and sheet-like networks. In addition to its biochemical composition, including the covalent intermolecular cross-linkages, the ECM is also characterized by its biophysical parameters, such as topography, molecular density, stiffness/rigidity and tension. Taking these biochemical and biophysical parameters into consideration, the ECM is very versatile and undergoes constant remodeling. This review focusses on this remodeling of the ECM under the influence of a primary solid tumor mass. Within this tumor stroma, not only the cancer cells but also the resident fibroblasts, which differentiate into cancer-associated fibroblasts (CAFs), modify the ECM. Growth factors and chemokines, which are tethered to and released from the ECM, as well as metabolic changes of the cells within the tumor bulk, add to the tumor-supporting tumor microenvironment. Metastasizing cancer cells from a primary tumor mass infiltrate into the ECM, which variably may facilitate cancer cell migration or act as barrier, which has to be proteolytically breached by the infiltrating tumor cell. The biochemical and biophysical properties therefore determine the rates and routes of metastatic dissemination. Moreover, primed by soluble factors of the primary tumor, the ECM of distant organs may be remodeled in a way to facilitate the engraftment of metastasizing cancer cells. Such premetastatic niches are responsible for the organotropic preference of certain cancer entities to colonize at certain sites in distant organs and to establish a metastasis. Translational application of our knowledge about the cancer-primed ECM is sparse with respect to therapeutic approaches, whereas tumor-induced ECM alterations such as increased tissue stiffness and desmoplasia, as well as breaching the basement membrane are hallmark of malignancy and diagnostically and histologically harnessed.