Mini Reviews in Medicinal Chemistry - Volume 10, Issue 5, 2010

BIOGRAPHY Fazlul H. Sarkar, Ph.D. is a professor of pathology at Karmanos Cancer Center, Wayne State University School of Medicine with a track-record of cancer research for 30 years. His research is focused on understanding the role of a “master” transcription factor, NF-κB and the regulation of its upstream and downstream signaling molecules in solid tumors. Moreover, his focused research has also been directed toward elucidating the molecular mechanisms of action of “natural agents” and synthetic small molecules for cancer prevention and therapy. He has done a tremendous amount of work in vitro and in vivo, documenting that several “natural agents” could be useful for chemopreventive research. Most importantly, his work has led to the discovery of the role of chemopreventive agents in sensitization of cancer cells (reversal of drug-resistance) to conventional therapeutics (chemo-radiotherapy). He is one of the pioneers in developing natural agents such as Isoflavones, Curcumin and Indole compounds like DIM (B-DIM) for clinical use, and his basic science research findings led to the initiation of multiple Clinical Trials in breast, pancreas and prostate cancers at the Karmanos Cancer Institute. He is a perfect example of a true translational researcher bringing his laboratory research findings into clinical practice. Dr. Sarkar is also involved in several collaborative projects including breast, lung and pancreatic cancer for both pre-clinical and phase II clinical trials with other scientists within the institution as well as collaborative work with basic scientists and physician scientists at the MD Anderson Cancer Center. He has published over 350 original scientific articles and written more than 50 review articles and book chapters. He has been continuously funded by NCI, NIH and the Department of Defense (DOD). Dr. Sarkar has trained numerous pre-doctoral and post-doctoral students throughout his last 30 years of cancer research career. In addition, Dr. Sarkar has served and still serving on a number of departmental, university and national committees, and continues to serve both NIH and DOD study sections including NIH program projects, SPORE grants and Cancer Center Core grants (site visit) for many NCI-designated Comprehensive Cancer Center. He serves in an important role as a Senior Editor of the journal “Molecular Cancer Therapeutics” and Associate Editor and in the Editorial board of many biomedical journals. EDITORIAL PERSPECTIVES A series of thirteen articles has been assembled for the theme “Recent Trends in Anti-Cancer Drug Discovery” for the journal of “Mini Reviews in Medicinal Chemistry (MRMC)”. These articles are uniquely focused on anti-cancer drugs especially those that are either derived from “natural sources”, i.e., “natural agents” or their synthetic analogs and/or novel synthetic and targeted agents with anti-cancer activity. These articles represent “state-of-our-knowledge” on emerging concepts in drug discovery which are intimately linked with the biology of cancer cells at large. This thematic issue is published as volume 10 in two parts, the first part is published as issue 5 and the second part is published as issue 6. The first in this series is from the laboratory of Dr. Anant whose article is focused on “Cancer Stem Cells: a novel paradigm for cancer prevention and treatment”, which is an emerging area in cancer research especially because targeted killing of cancer stem-like cells are imperative toward achieving complete eradication of tumors. In addition to the discussion on the role of cancer stem-like cells in drug development and therapy, the authors have also described the role of natural agents in targeted killing of cancer stem-like cells for cancer prevention and therapy. The next article is from the laboratory of the editor, Dr. Sarkar of this thematic issue of MRMC who provided the perspectives on chemopreventive and therapeutic potential of curcumin analogs in medicinal chemistry. Although naturally found “Curcumin” has been extensively investigated, the lack of systemic as well as target tissue bioavailability of curcumin limits its application in humans. Therefore, many approaches has been taken in recent years for improving the bioavailability of curcumin including novel synthesis of its structural analog, which has been described in this article focusing on prevention of tumor progression and/or treatments of human malignancies....

Cancer is the second leading cause for mortality in US only after heart disease and lacks a good or effective therapeutic paradigm. Despite the emergence of new, targeted agents and the use of various therapeutic combinations, none of the treatment options available is curative in patients with advanced cancer. A growing body of evidence is supporting the idea that human cancers can be considered as a stem cell disease. Malignancies are believed to originate from a fraction of cancer cells that show self renewal and pluripotency and are capable of initiating and sustaining tumor growth. The cancer-initiating cells or cancer stem cells were originally identified in hematological malignancies but is now being recognized in several solid tumors. The hypothesis of stem cell-driven tumorigenesis raises questions as to whether the current treatments, most of which require rapidly dividing cells are able to efficiently target these slow cycling tumorigenic cells. Recent characterization of cancer stem cells should lead to the identification of key signaling pathways that may make cancer stem cells vulnerable to therapeutic interventions that target drug-effluxing capabilities, anti-apoptotic mechanisms, and induction of differentiation. Dietary phytochemicals possess anti-cancer properties and represent a promising approach for the prevention and treatment of many cancers.

Curcumin is a natural polyphenol derived from the plant Curcuma longa, commonly called turmeric. Extensive research over past 50 years has indicated that this polyphenol is highly pleiotropic molecule capable of preventing and treating various cancers. The anticancer potential of Curcumin is severely affected by its limited systemic and target tissue bioavailability and rapid metabolism. In the present review article, we provide a summarized account of different drug delivery systems employed for tackling the problem of curcumin's bioavailability such as liposomes, phospholipid complexes and nanoparticles. Concomitantly we have reviewed the large volume of literature reports describing structural modifications of Curcumin and the anticancer potential of its analogs. Some of the difluorocurcumin analogs allowing longer circulation times and preferential accumulation in the pancreas seem to offer promising leads for conducting first in-depth animal studies and subsequently clinical trials for the use of these analogs for prevention of tumor progression and/or treatments of human malignancies.

Our ability to detect and treat most primary cancers has improved dramatically given the advances in our understanding of cancer biology. However, with increased life expectancy and our inability to treat or cure advanced stages of cancers, the number of cancer-related deaths is expected to double in the next decade. Epidemiological studies suggest that dietary factors are an important aspect that influences cancer risk. Despite a lack of scientific evidence in most cases, cancer patients have whole-heartedly accepted the concept of “alternative medicine” using natural compounds and spent more than $1B a year on herbal supplements. Given the significant toxicity-associated problems with current long-term standard of care, scientifically validated natural supplements can serve as novel and effective alternative strategies for effective cancer management. We will discuss the utility of natural products in modulating critical signaling pathways for effective cancer prevention with special emphasis on prostate cancer and their potential translational benefit.

The antitumor activity of indole-3-carbinol is attributable to its ability to interfere with multiple oncogenic signaling pathways governing cell cycle progression, survival, invasion, and other aggressive phenotypes of cancer cells, especially those mediated by EGFR/Src, Akt, NF-κB, endoplasmic reticulum stress, and nuclear receptors. This broad spectrum of antitumor activities in conjunction with its metabolic instability constitutes the rationale for the structural modifications of indole-3-carbinol and its metabolite diindolylmethane to develop novel classes of antitumor agents with improved potency and distinct mechanisms. Thus, this minireview focuses on the chemical biology of the lead optimization of these indole derivatives.

One of the hallmarks of cancer is the uncontrolled cell proliferation which causes more deaths among the human diseases throughout the globe. One in eight deaths worldwide are due to cancer, it is the second and third leading cause of death in economically developed and developing countries, respectively. As it is caused by both external and internal factors, a balanced approach to cancer control includes prevention, early detection, and effective treatment. In the treatment of cancer, chemotherapy is one of the practical methods and is widely used employing drugs that can destroy cancer cells by impeding their growth and reproduction. Despite the great strides made in the treatment of cancer over the past 50 years, it continues to be a major health concern and therefore, extensive efforts have been devoted to search for new scaffolds to develop chemotherapeutics. In this perspective, over the past two decades from this laboratory extensive efforts have been made in the development of new chemotherapeutic agents for the treatment of cancer. In this review, glimpses on types of current chemotherapeutic agents based on their action of inhibition and the new molecules that are being developed based on the scaffolds such as pyrrolo[2,1-c][1,4]benzodiazepines, podophyllotoxins, benzothiadiazine 1,1-dioxides, naphthalimides and monastrol across the world as well as in this laboratory have been articulated.

Benzoquinones are class of natural quinones found chiefly in higher plants, fungi, bacteria and animal kingdom. They are involved in important biological functions such as bioenergetic transport, oxidative phosphorylation and electron transport processes. In recent years it has become increasingly clear that some of them possess potent antioxidant, anti-inflammatory and anticancer activities. There is clearly a common thread running through these activities and there have been a large number of studies carried out to unravel the mechanisms of these activities. In the present review we have provided a brief account of these studies especially covering these aspects. Although antioxidant potentials of these compounds constitute the basis of their biological activities its nature and scope is dictated by many microscopic biological environments. One of the important advantages offered by these compounds is the ease with which they can be synthesized and chemically manipulated. This can easily provide impetus for further research in developing some potentially useful drug molecules.