Network insights on oxaliplatin anti‐cancer mechanisms

Abstract

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.

Effect of Oxaliplatin-Loaded Poly (d,l-Lactide-co-Glycolic Acid) (PLGA) Nanoparticles Combined with Retinoic Acid and Cholesterol on Apoptosis, Drug Resistance, and Metastasis Factors of Colorectal Cancer

“…OXA is a third-generation platinum drug, which inhibits DNA replication [46]. However, the obtained efficacy is suboptimal due to the aggressive side effects OXA and drug resistance of cancer cells [46][47][48]. The pro-apoptotic activities of NPs and OXA were analyzed by flow cytometry for both CT-26 and nontumor cells.…”

The potential role of Alu Y in the development of resistance to SN38 (Irinotecan) or oxaliplatin in colorectal cancer

“…Oxaliplatin is a platinum-based chemotherapeutic agent [ 38 ], which exerts its effects by interfering with the DNA replication and transcription machinery through nuclear DNA adduct formation [ 39 ]. In the clinic, oxaliplatin’s efficacy depends on combined use with 5-fluorouracil (5-FU) [ 40 ]. Capecitabine is a prodrug, that is enzymatically converted to 5-fluorouracil [ 41 ], which inhibits the production of nucleotide thymidine by inhibiting the enzyme thymidylate synthase [ 42 ].…”

Self-assembled nanoscale coordination polymers carrying oxaliplatin and gemcitabine for synergistic combination therapy of pancreatic cancer

“…Oxaliplatin exerts its effect by forming DNA adduct that interferes with DNA replication [43, 44]. However, only 5-10% of platin complex are covalently bounded to DNA, while 75-85% of drug is bounded to proteins, such as cysteine and methionine [45, 46]. Furthermore, tumor cells develop acquired platinum resistance, primarily from high expression levels of resistance genes [47].…”