Network insights on oxaliplatin anti-cancer mechanisms.
Oxaliplatin has been a crucial component of combination therapies since admission into the clinic causing modest gains in survival across multiple malignancies. However, oxaliplatin functions in a non-targeted manner, posing a difficulty in ascertaining precise efficacy mechanisms. While previously thought to only affect DNA repair mechanisms, Platinum-protein adducts (Pt-Protein) far outnumber Pt-DNA adducts leaving a big part of oxaliplatin function unknown. Through preliminary network modeling of high throughput data, this article critically reviews the efficacy of oxaliplatin as well as proposes a better model for enhanced efficacy based on a network approach. In our study, not only oxaliplatin's function in interrupting DNA-replication was confirmed, but also its role in initiating or intensifying tumorigenesis pathways was uncovered. From our data we present a novel picture of competing signaling networks that collectively provide a plausible explanation of chemotherapeutic resistance, cancer stem cell survival, as well as invasiveness and metastases. Here we highlight oxaliplatin signaling networks, their significance and the clinical implications of these interactions that verifies the importance of network modeling in rational drug design.
Department of Oncology, Karmanos Cancer Institute, Wayne State University, 4100 John R, HWCRC, Room 732, Detroit, MI, 48201, USA. mohammar@karmanos.org.
Osama M
OM
Alian
Asfar S
AS
Azmi
Ramzi M
RM
Mohammad