The potentials of carbon monoxide-releasing molecules in cancer treatment: An outlook from ROS biology and medicine

Abstract

Carbon monoxide (CO) is now well recognized a pivotal endogenous signaling molecule in mammalian lives. The proof-of-concept employing chemical carriers of exogenous CO as prodrugs for CO release, also known as CO-releasing molecules (CO-RMs), has been appreciated. The major advantage of CO-RMs is that they are able to deliver CO to the target sites in a controlled manner. There is an increasing body of experimental studies suggesting the therapeutic potentials of CO and CO-RMs in different cancer models. This review firstly presents a short but crucial view concerning the characteristics of CO and CO-RMs. Then, the anticancer activities of CO-RMs that target many cancer hallmarks, mainly proliferation, apoptosis, angiogenesis, and invasion and metastasis, are discussed. However, their anticancer activities are varying and cell-type specific. The aerobic metabolism of molecular oxygen inevitably generates various oxygen-containing reactive metabolites termed reactive oxygen species (ROS) which play important roles in both physiology and pathophysiology. Although ROS act as a double-edged sword in cancer, both sides of which may potentially have been exploited for therapeutic benefits. The main focus of the present review is thus to identify the possible signaling network by which CO-RMs can exert their anticancer actions, where ROS play the central role. Another important issue concerning the potential effect of CO-RMs on the aerobic glycolysis (the Warburg effect) which is a feature of cancer metabolic reprogramming is given before the conclusion with future prospects on the challenges of developing CO-RMs into clinically pharmaceutical candidates in cancer therapy.

Keywords: Apoptosis; Carbon monoxide; Carbon monoxide-releasing molecules; Pro-tumorigenic pathways; Reactive oxygen species; Warburg effect.

Graphical abstract

Fig. 1

The dose-response of CO in mammalian systems. The measurement of blood COHb level is a useful tool to assess the actions of CO. Under physiological conditions, CO is endogenously produced at very low levels that lead to about 0.5–0.8% COHb in the blood. This gaseous molecule acts as an important signaling messenger that regulates multiple processes. For therapeutic purposes, the higher concentrations of CO are required. It has been suggested that pharmacological actions of CO are in concomitance with approximately 10–15% COHb. Moving upward, significant symptoms of CO poisoning are detectable at 20% COHb, and death may occur at the levels exceeding 60%.

Fig. 2

The two-dimensional schematic of the structure of CO-RMs and their modes of action of CO release. Surrounding the core, the CORM sphere (or coordination sphere) constitutes the inner part of CO-RM, and the drug sphere creates the outer. The CORM sphere determines the stoichiometry, the kinetics, and the trigger mechanism of CO release, while the drug sphere directs the pharmacological profile of CO-RMs. Upon their administration into the body, most CO-RMs induce the ligand substitution/exchange reaction with the medium to spontaneously liberate CO from the CORM sphere. Another potential mode of action is the photochemical external activation, resulting in the compounds so-called photoCO-RMs. Certain internal initiators such as pH, redox milieu, and enzymes have been exploited as trigger mechanisms; however, the study is still at preliminary stage. Note: C: core; CO: CO ligand; L: co-ligand.

Fig. 3

Proposed mechanisms behind the anticancer activities of CO released from CO-RMs. The anticancer actions of CO-RMs is mainly associated with the inhibition of cell proliferation, angiogenesis, and invasion and metastasis as well as the induction of apoptosis. As mitochondria and NADPH oxidase, which are known the major sources of intracellular ROS, have been implicated as the targets of CO action, ROS seem likely to play important roles in the signaling pathways by which CO-RMs exert their actions. While CO may downregulate the ROS generation to inhibit different pro-tumorigenic pathways, CO at higher concentrations can increase the levels of ROS to induce the mitochondrial-mediated apoptotic pathway. Thus, CO-RMs can take advantages of both sides of ROS to provide therapeutic benefits in specific scenario. Moreover, CO-RMs may also act as promising candidates that target the cancer metabolic reprogramming by eliciting anti-Warburg effect.