p38MAPK and Chemotherapy: We Always Need to Hear Both Sides of the Story

Abstract

The p38MAPK signaling pathway was initially described as a stress response mechanism. In fact, during previous decades, it was considered a pathway with little interest in oncology especially in comparison with other MAPKs such as ERK1/2, known to be target of oncogenes like Ras. However, its involvement in apoptotic cell death phenomena makes this signaling pathway more attractive for many cancer research laboratories. This apoptotic role allows to establish a link between p38MAPK and regular chemotherapeutic agents such as Cisplatin or base analogs (Cytarabine, Gemcitabine or 5-Fluorouracil) which are currently used in hospitals across the world. In fact, and more recently, p38MAPK has also been connected with targeted therapies like tyrosine kinase inhibitors (vg. Imatinib, Sorafenib) and, to a lesser extent, with monoclonal antibodies. In addition, the oncogenic or tumor suppressor potential of this signaling pathway has aroused the interest of the scientific community in evaluating p38MAPK as a novel target for cancer therapy. In this review, we will summarize the role of p38MAPK in chemotherapy as well as the potential that p38MAPK inhibition can bring to cancer therapy. All the evidences suggest that p38MAPK could be a double-edged sword and that the search for the most appropriate candidate patients, depending on their pathology and treatment, will lead to a more rational use of this new therapeutic tool.

Novel Indole-based Tambjamine-Analogues Induce Apoptotic Lung Cancer Cell Death through p38 Mitogen-Activated Protein Kinase Activation

“…Likewise, genotoxic agents (cisplatin and oxaliplatin) and topoisomerase II inhibitors (doxorubicin) were also able to activate p38 MAPK route (43,44). Nowadays, a dual-role of this route is known with the action as tumor suppressor or tumor promoter largely depending on the type of cancer and tumor stage (45). Interestingly, our results have shown a robust p38 MAPK activation and using the specific p38 MAPK inhibitor, SB202190, we were able to significantly restore cell viability.…”

The p38 MAPK Signaling Activation in Colorectal Cancer upon Therapeutic Treatments

“…5-FU has been the clinical practice for the management of CRC (and other solid malignancies) for decades, and is currently used in combination with other chemotherapeutic agents [20,21]. 5-FU is a pyrimidine analogue that exerts its antitumoral function via both inhibiting thymidylate synthase, a crucial enzyme in DNA replication, and being misincorporated during polynucleotide biosynthesis, resulting into DNA damage and, ultimately, apoptosis [22]. The effects of 5-FU on molecular stress pathways have long been investigated: indeed, reports are quite unanimous about p38 MAPK being phosphorylated and activated upon 5-FU exposure in several different cell-types [23,24].…”

The p38 pathway, a major pleiotropic cascade that transduces stress and metastatic signals in endothelial cells

“…Apoptosis is a major mechanism of cell death in response to anticancer agents and several studies already reported the role of p38 in modulating the chemotherapeutic response of both conventional treatment and novel agents including tyrosine kinase inhibitors (TKI) as well as monoclonal antibodies [ 272 ]. p38 has been implied in cell apoptosis mediated by cis-platinium and 5-fluorouracil (5-FU) in breast and colon cancer cell lines [ 272 ]. Furthermore, inhibition of p38 has been associated with resistance to gemcitabine and cytarabine [ 272 , 273 ].…”