Advances in Translational Pharmacological Investigations in Identifying and Validating Molecular Targets of Natural Product Anticancer Agents

Junxian      Yu; Subhasree   A.   Nag; Ruiwen      Zhang

Abstract

Natural products with biodiversity and chemical variations present a rich source for the discovery and development of new therapeutic and preventive drugs. Bioactive components derived from natural medicines including traditional Chinese medicine have been widely used for the screening of effective and safe anticancer drugs. Meanwhile, the investigation on mechanism of action (MOA) of natural bioactive components has a critical role in identifying and validating new molecular targets of those anticancer agents. Considering the high complexity of pharmacodynamic (PD) and pharmacokinetic (PK) characteristics of natural product anticancer agents, there are several major challenges in understanding mechanisms of action in vitro and in vivo for these agents. The recent rapid progress made in molecular and cell biology, genetics and genomics, and translational medicine, preclinical investigations provides an impetus for a better understanding of mechanisms of action and structure-activity relationships (SAR) of natural products. In addition, the simultaneous evaluation of PD-PK characterizations would allow a full assessment of the safety, efficacy, and indication of natural product anticancer drugs in various regimens and in various clinical settings. In this review, we provide a brief summary for recent advances in translational pharmacology, focusing on target validation and PK-PD, MOA, and SAR. Several examples for clinically used agents, and cancer preventive agents and therapeutic agents under preclinical and clinical development are used to illustrate the importance of such translational research and challenges we are facing.

Keywords: Anticancer agents, arsenic trioxide, artemisinin, curcumin, genistein, ginseng, molecular targeting, natural products, structure-activity relationship, traditional chinese medicine, translational pharmacology.