Anticancer properties of nimbolide and pharmacokinetic considerations to accelerate its development.

Lingzhi Wang,Boon Cher Goh,Paul Chi-Lui Ho,Wei Peng Yong,Win Lwin Thuya,Andrea Li-Ann Wong,Soo Chin Lee,Ross Soo,Do Dang Khoa Phan,Gautam Sethi,Jingwen Zhang,Pei-Shi Ong

doi:10.18632/oncotarget.8316

Abstract

Nimbolide is one of the main components in the leaf extract of Azadirachta indica (A. indica). Accumulating evidence from various in vitro and in vivo studies indicates that nimbolide possesses potent anticancer activity against several types of cancer and also shows potential chemopreventive activity in animal models. The main mechanisms of action of nimbolide include anti-proliferation, induction of apoptosis, inhibition of metastasis and angiogenesis, and modulation of carcinogen-metabolizing enzymes. Although multiple pharmacodynamic (PD) studies have been carried out, nimbolide is still at the infant stage in the drug development pipeline due to the lack of systematic pharmacokinetic (PK) studies and long-term toxicological studies. Preclinical PK and toxicological studies are vital in determining the dosage range to support the safety of nimbolide for first-in-human clinical trials. In this review, we will provide a comprehensive summary for the current status of nimbolide as an anticancer and chemopreventive lead compound, and highlight the importance of systematic preclinical PK and toxicological studies in accelerating the process of application of nimbolide as a therapeutic agent against various malignancies.

Highlights

Azadirachtaindica, commonly known as neem, is a tree belonging to the Meliceae family, which is native to India and the Indian Subcontinent
In accordance with the drug development pipeline [14], nimbolide is at the stage of preclinical pharmacological investigation, where pharmacodynamics (PD), toxicology, and pharmacokinetic (PK) studies should be performed before the drug can proceed to the clinical testing phase
The objectives of the present review are to summarize the current status of nimbolideas a chemopreventive and chemotherapeutic agent in specific cancer types based on pre-clinical studies, as well as to highlight the importance of performing toxicological and PK studies that will lay the foundation for its early-phase clinical investigation

Summary

Introduction

Azadirachtaindica, commonly known as neem, is a tree belonging to the Meliceae family, which is native to India and the Indian Subcontinent. The anticancer and cancer preventive effects of nimbolide were observed in several animal studies [11-13], thereby providing strong evidence to support its further development as a therapeutic agent against cancer. In accordance with the drug development pipeline [14], nimbolide is at the stage of preclinical pharmacological investigation, where pharmacodynamics (PD), toxicology, and pharmacokinetic (PK) studies should be performed before the drug can proceed to the clinical testing phase. The development of various separation techniques [15-18] has facilitated a highly efficient extraction of nimbolide for use in many in vitro experiments to elucidate its potential therapeutic actions, the absence of information on its absorption, distribution, metabolism, and elimination (ADME), as well as its toxicity, in turn hampers further clinical studies on this natural compound. The objectives of the present review are to summarize the current status of nimbolideas a chemopreventive and chemotherapeutic agent in specific cancer types based on pre-clinical studies, as well as to highlight the importance of performing toxicological and PK studies that will lay the foundation for its early-phase clinical investigation

Objectives

Methods

Findings

Conclusion