title: The pivotal role of intracellular calcium in oxaliplatin-induced inhibition of neurite outgrowth but not cell death in differentiated PC12 cells.
abstract: The antineoplastic efficacy of oxaliplatin, a widely used anticancer drug, is restricted by its adverse effects such as peripheral neuropathy. Infusing a combination of calcium gluconate and magnesium sulfate (Ca/Mg) suppresses the acute neurotoxic side effects of oxaliplatin, although the mechanism is unclear. To elucidate the molecular mechanisms of oxaliplatin-induced neurotoxicity and the effects of Ca/Mg against this toxicity, we examined the effect of Ca/Mg on oxaliplatin-induced inhibition of neurite outgrowth in PC12 cells, a commonly used neuronal cell model. Oxaliplatin and oxalate suppressed nerve growth factor (NGF)-induced neurite outgrowth and reduced the NGF-mediated increase in the intracellular calcium concentration [Ca(2+)](i). A calcium-chelating agent, BAPTA/AM, also exhibited similar inhibitory effects on neurite outgrowth and [Ca(2+)](i). The addition of Ca/Mg attenuated these inhibitions induced by oxaliplatin and oxalate. The NGF-induced upregulation of growth-associated protein-43 (GAP-43) was suppressed by oxaliplatin and oxalate. Oxaliplatin, but not oxalate, suppressed NGF-stimulated extracellular signal-regulated kinase activation, and this inhibition was not affected by Ca/Mg. Ca/Mg did not modify the oxaliplatin-induced loss of cell viability or apoptosis in PC12 or HCT-116 cells, a human colorectal cancer cell line. These results suggest that the inhibition of neurite outgrowth but not tumor cell death induced by oxaliplatin is partly associated with reductions in [Ca(2+)](i) and GAP-43 expression, and this inhibition was suppressed by the addition of Ca/Mg. Therefore, it may be assumed that Ca/Mg is useful for protecting against oxaliplatin-induced neurotoxicity without reducing the antitumor activity of oxaliplatin.
authors: Department of Pharmacy Practice and Science, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors: Miki
authors: M
authors: Takeshita
authors: Yoshiko
authors: Y
authors: Banno
authors: Mitsuhiro
authors: M
authors: Nakamura
authors: Mayuko
authors: M
authors: Otsuka
authors: Hitomi
authors: H
authors: Teramachi
authors: Teruo
authors: T
authors: Tsuchiya
authors: Yoshinori
authors: Y
authors: Itoh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002125:Calcium Gluconate / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002614:Chelating Agents / Q000378:metabolism / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D019922:GAP-43 Protein / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D045325:HCT116 Cells; D006801:Humans; D008278:Magnesium Sulfate / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D020932:Nerve Growth Factor / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000494:pharmacology*; D019815:Oxalic Acid / Q000378:metabolism; D000077150:Oxaliplatin; D016716:PC12 Cells; D051381:Rats; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D002614:Chelating Agents; D019922:GAP-43 Protein; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D008278:Magnesium Sulfate; D020932:Nerve Growth Factor; D019815:Oxalic Acid; D048049:Extracellular Signal-Regulated MAP Kinases; D002125:Calcium Gluconate; D002118:Calcium