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: Miki Takeshita, Yoshiko Banno, Mitsuhiro Nakamura, Mayuko Otsuka, Hitomi Teramachi, Teruo Tsuchiya, Yoshinori Itoh
• Journal: Chemical research in toxicology (Chem Res Toxicol) Vol. 24 Issue 11 Pg. 1845-52 (Nov 21 2011) ISSN: 1520-5010 [Electronic] United States
• PMID: 21981408 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Chelating Agents
• GAP-43 Protein
• Organoplatinum Compounds
• Oxaliplatin
• 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester
• Egtazic Acid
• Magnesium Sulfate
• Nerve Growth Factor
• Oxalic Acid
• Extracellular Signal-Regulated MAP Kinases
• Calcium Gluconate
• Calcium

Topics

• Animals
• Antineoplastic Agents (adverse effects, pharmacology)
• Calcium (metabolism)
• Calcium Gluconate (metabolism, pharmacology, therapeutic use)
• Cell Death (drug effects)
• Cell Differentiation (drug effects)
• Chelating Agents (metabolism, pharmacology)
• Egtazic Acid (analogs & derivatives, metabolism, pharmacology)
• Extracellular Signal-Regulated MAP Kinases (genetics, metabolism)
• GAP-43 Protein (genetics, metabolism)
• Gene Expression
• HCT116 Cells
• Humans
• Magnesium Sulfate (metabolism, pharmacology, therapeutic use)
• Neoplasms (drug therapy, metabolism, pathology)
• Nerve Growth Factor (pharmacology)
• Neurites (drug effects, metabolism)
• Organoplatinum Compounds (adverse effects, pharmacology)
• Oxalic Acid (metabolism)
• Oxaliplatin
• PC12 Cells
• Rats
• Signal Transduction