Low-dose cisplatin protects human neuroblastoma SH-SY5Y cells from paclitaxel-induced apoptosis

Abstract

Combined anticancer therapy using platinum compounds and antitubulins has increased the risk of neurotoxicity. However, the combination of low-dose cisplatin (CDDP) with toxic doses of paclitaxel significantly reduces cellular death in a human neuroblastoma SH-SY5Y cell line. To analyze the mechanisms of this protection, we evaluated various signaling molecules possibly involved in apoptosis and some relevant cell cycle regulatory proteins. CDDP does not interfere with the tubulin-stabilizing action of paclitaxel. The evaluation of molecular pathways involved in apoptosis indicates that the Bcl-2 but not the caspases may be involved in the CDDP protection of paclitaxelinduced apoptosis. The increase in p53 protein and its nuclear accumulation suggests a possible involvement of p53 in CDDP protection. The use of the chemical inhibitor of p53, pifithrin A, excluded this possibility. The study of cyclins and the flow cytometric analysis (fluorescenceactivated cell sorting) suggest that CDDP exerts a protective action by blocking cells early in the cell cycle.

Neurotoxic effects of antineoplastic drugs: the lesson of pre-clinical studies

“…The length of neurites in SH-SY5Y cell cultures treated with different concentrations of antineoplastic drugs (compared with the length of neurites of control cultures) allows a wide spectrum of concentrations of the drugs to be tested quickly (25). Moreover, this in vitro model can be used to investigate the cellular and molecular mechanisms implicated in the drugs' neurotoxicity (26)(27)(28)(29).…”

Selective reduction of extracellular signal-regulated protein kinase (ERK) phosphorylation in squamous cell carcinoma of the larynx

“…The c-Jun N-terminal kinases (JNK1/2) or the stress-activated protein kinase (SAPK) were first identified by their ability to phosphorylate the c-Jun transcription factor following exposure to growth factors or after the expression of transforming oncogenes (16). JNK/SAPK are related to cell stress response and they are known for activating several factors such as ATF2, Bcl2, p53 as well as several oncogenes (17)(18)(19). A third group collectively known as p38 are activated by proinflammatory cytokines and chemicals and affect radiation-and druginduced cell death (20).…”