Prof. Edy Meiyanto

Gadjah Mada University, Indonesia

Cancer Chemoprevention Research Center Faculty of Pharmacy
Universitas Gadjah Mada

Abstract

Cancer ROS Metabolism as a Target for Anticancer Development

Cancer ROS metabolism is an essential target of anticancer development. Hanahan and Weinberg introduce cancer metabolism as the role of cancer to deregulate cellular energetic. Concept of cancer metabolism is a high metabolism activity in a cancer cell as a consequence of genetic, metabolic and microenvironment-associated alterations resulting in accumulation of Reactive Oxygen Species (ROS). High level of ROS or RCS (Reactive Carbonyl Species) produces reactive aldehydes leading to the damage of cellular macromolecules and induces cellular physiological changes such as authopagy, senescence, apoptosis, and DNA adduct. Various carbonyl-metabolizing enzyme are produced by cancer cells to decrease ROS accumulation on the cancer cells. Therefore, inducing ROS accumulation through inhibition of carbonyl-metabolizing enzyme exhibits as more strategic action than common anticancer mechanism. Several agents are known to possess ROS inductor or pro-oxidant. Doxorubicin and Cisplatin, the common chemotherapeutic agents, induce ROS accumulation on cancer cells then induces apoptosis, G2/M phase arrest, and DNA intercalation. However, Doxorubicin and cisplatin mediated hepatotoxicity, cardiotoxicity, and nefrotoxicity due to unselectiviy of ROS accumulation on normal cells. An unique natural compound, curcumin also has been revealed to perform as pro-oxidant agent. Based on molecular docking study, curcumin occupied the site of NAPDH of CBR1, interacted with glutathione-S-transferase Pi (GST-PI) better than its native ligand, interacted with ALR2 in a closed type of conformation, and interacted with GLO1 through hydrophobic interactions. Curcumin and its analogues (Pentagamuvonon-1 (PGV-1) and Pentagamaboronon-0 (PGB-0)) increased ROS expression on several cancer cells. Potential inhibition study of carbonyl-metabolizing enzyme revealed that curcumin inhibits CBR1, GLO1, NQO1, and ALR2 enzymatic activity. Curcumin was known as a potent inhibitor of GSTs and Prdx-1 is the most abundant protein pulled by curcumin. Study on K562 cells indicating the molecular mechanism underlying antiproliferative activity of curcumin is revealed by interaction to several carbonyl-metabolizing enzymes. Hence, developing agents targeted on cancer metabolism exhibit as a potential strategy of the novel anticancer agent.

Keywords: Cancer Metabolism, ROS, Carbonyl-Metabolizing Enzyme, Curcumin

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