Network insights on oxaliplatin anti-cancer mechanisms

Oxaliplatin, recognized as a DNA intercalating agent, is a platinum coordinated complex that is used in conjunction with different chemotherapies for the treatment of various cancers [1]. In general, oxaliplatin exhibits more efficacious behavior in vitro than its close platinum based counterpart, cisplatin. These effects were demonstrated through IG50 experiments on a standard NCI drug screen panel (Figure 1). Oxaliplatin exerts its effects by interfering with DNA replication and transcription machinery through nuclear DNA adduct formation [2]. These Pt-DNA adducts typically are in the form of Pt-Guanine-Guanine (Pt-GG) bonding (Figure 2B) [3]. Ultimately, Pt-DNA complexes at the nucleotide level will either activate DNA repair mechanisms or apoptotic pathways. Interestingly, it has been shown that contrary to its DNA binding capacity, the rate of protein binding of oxaliplatin may be significantly higher than its covalent binding to DNA (in cisplatin adducts, a similarly acting compound, 75-85% of covalent binding occurs with proteins compared with 5-10% in DNA) exhibiting significant differences when compared to DNA lesions [4]. For example, in many cancers there is an over expression of DNA repair proteins such as DNA pol β and knock down or under expression of this protein results in increased sensitivity to oxaliplatin induced DNA damage [5]. These findings build a compelling case for the exploration of protein expression profiles of oxaliplatin treatment, as the specificity of oxaliplatin is not limited to Pt-DNA adducts. Thus, a further examination of oxaliplatin and other platinum compounds used in adjuvant therapies effect on protein expressions is vital to understanding efficacy or lack thereof.Clinically, the use of oxaliplatin is efficacious only when combined with other agents such as 5-fluorouracil (5-FU) and leucovorin (LV). Prior to entry into US clinics, oxaliplatin was used against colorectal cancer where it did not show, any significant improveme