Plant-Derived Anticancer Agents: Lessons from the Pharmacology of Geniposide and Its Aglycone, Genipin

Abstract

For centuries, plants have been exploited by mankind as sources of numerous cancer chemotherapeutic agents. Good examples of anticancer compounds of clinical significance today include the taxanes (e.g., taxol), vincristine, vinblastine, and the podophyllotoxin analogues that all trace their origin to higher plants. While all these drugs, along with the various other available therapeutic options, brought some relief in cancer management, a real breakthrough or cure has not yet been achieved. This critical review is a reflection on the lessons learnt from decades of research on the iridoid glycoside geniposide and its aglycone, genipin, which are currently used as gold standard reference compounds in cancer studies. Their effects on tumour development (carcinogenesis), cancer cell survival, and death, with particular emphasis on their mechanisms of actions, are discussed. Particular attention is also given to mechanisms related to the dual pro-oxidant and antioxidant effects of these compounds, the mitochondrial mechanism of cancer cell killing through reactive oxygen species (ROS), including that generated through the uncoupling protein-2 (UCP-2), the inflammatory mechanism, and cell cycle regulation. The implications of various studies for the evaluation of glycosidic and aglycone forms of natural products in vitro and in vivo through pharmacokinetic scrutiny are also addressed.

Keywords: apoptosis; cancer; carcinogenesis; genipin; geniposide; metastasis; reactive oxygen species; uncoupling protein 2.

Figure 1

Structures of geniposide and its analogues. Geniposide is a natural analogue or methyl ester of geniposidic acid. Genipin is the aglycone of geniposide which is also present in plants, while penta-acetyl geniposide is a synthetic derivative widely employed in anticancer activity studies.

Figure 2

Transport mechanisms of geniposide and genipin. The absorption of geniposide, which is predominantly present in plant extracts, could be enhanced by transformation in the gut through the action of bacterial β-glucosidase enzymes. Other preparations, such as borneaol or crude plant extracts, could increase the absorption from the gut. The bioactive molecule, genipin, is highly non-polar and water insoluble, and a formulation strategy is required to maximize its absorption.

Figure 3

The various stages of cancer development and their potential modulation by genipin and analogs. Genipin/geniposide appear to target almost all stages of cancer development via multiple mechanisms.

Figure 4

Targeting UCP2 by genipin in cancer. The electron transport chain in the mitochondria comprises complexes I–IV that transfer electrons from NADH through a series of oxidation–reduction reactions. The generation of the (H⁺) electrochemical gradient by the coordinated action of complexes (I, II, and IV) allows coupling with phosphorylation via ATP synthase. In addition to O₂ serving as a final electron acceptor at complex IV, its premature reduction at complexes I and III could lead to O₂⁻ formation. UCP2, which is excessively expressed in cancer cells, uncouples the process by creating a (H⁺) leak and reducing the mitochondrial membrane potential. This mechanism, exploited by cancer cells as a survival factor via reducing ROS generation, is targeted by genipin. CoQ, coenzyme Q and Cyt C, cytochrome C.

Figure 5

The dual effect of genipin/geniposide on ROS. The plus (+) sign indicates potentiation while minus (−) sign indicates inhibition.