The ionophore thiomaltol induces rapid lysosomal accumulation of copper and apoptosis in melanoma

Ottis Scrivner; Long Dao; M. Karen Newell-Rogers; Babbak Shahandeh; Frank L. Meyskens; Susan Kurumi Kozawa; Feng Liu-Smith; Germán Plascencia-Villa; Miguel José-Yacamán; Shang Jia; Christopher J. Chang; Patrick J. Farmer

doi:10.1093/mtomcs/mfab074

The ionophore thiomaltol induces rapid lysosomal accumulation of copper and apoptosis in melanoma

Ottis Scrivner, Long Dao, M. Karen Newell-Rogers, Babbak Shahandeh, Frank L. Meyskens, Susan Kurumi Kozawa, Feng Liu-Smith, Germán Plascencia-Villa, Miguel José-Yacamán, Shang Jia, Christopher J. Chang, Patrick J. Farmer

Applied Physics and Materials Science

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

In this report, we investigate the toxicity of the ionophore thiomaltol (Htma) and Cu salts to melanoma. Divalent metal complexes of thiomaltol display toxicity against A375 melanoma cell culture resulting in a distinct apoptotic response at submicromolar concentrations, with toxicity of Cu(tma)₂ > Zn(tma)₂ >> Ni(tma)₂. In metal-chelated media, Htma treatment shows little toxicity, but the combination with supplemental CuCl₂, termed Cu/Htma treatment, results in toxicity that increases with suprastoichiometric concentrations of CuCl₂ and correlates with the accumulation of intracellular copper. Electron microscopy and confocal laser scanning microscopy of Cu/Htma treated cells shows a rapid accumulation of copper within lysosomes over the course of hours, concurrent with the onset of apoptosis. A buildup of ubiquitinated proteins due to proteasome inhibition is seen on the same timescale and correlates with increases of copper without additional Htma.

Original language	English (US)
Article number	mfab074
Journal	Metallomics
Volume	14
Issue number	1
DOIs	https://doi.org/10.1093/mtomcs/mfab074
State	Published - Jan 1 2022

Keywords

apoptosis
copper ionophore
melanoma
proteasome inhibition
thiomaltol

ASJC Scopus subject areas

General Medicine

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10.1093/mtomcs/mfab074

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Scrivner, O., Dao, L., Newell-Rogers, M. K., Shahandeh, B., Meyskens, F. L., Kozawa, S. K., Liu-Smith, F., Plascencia-Villa, G., José-Yacamán, M., Jia, S., Chang, C. J., & Farmer, P. J. (2022). The ionophore thiomaltol induces rapid lysosomal accumulation of copper and apoptosis in melanoma. Metallomics, 14(1), Article mfab074. https://doi.org/10.1093/mtomcs/mfab074

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abstract = "In this report, we investigate the toxicity of the ionophore thiomaltol (Htma) and Cu salts to melanoma. Divalent metal complexes of thiomaltol display toxicity against A375 melanoma cell culture resulting in a distinct apoptotic response at submicromolar concentrations, with toxicity of Cu(tma)2 > Zn(tma)2 >> Ni(tma)2. In metal-chelated media, Htma treatment shows little toxicity, but the combination with supplemental CuCl2, termed Cu/Htma treatment, results in toxicity that increases with suprastoichiometric concentrations of CuCl2 and correlates with the accumulation of intracellular copper. Electron microscopy and confocal laser scanning microscopy of Cu/Htma treated cells shows a rapid accumulation of copper within lysosomes over the course of hours, concurrent with the onset of apoptosis. A buildup of ubiquitinated proteins due to proteasome inhibition is seen on the same timescale and correlates with increases of copper without additional Htma.",

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AU - Meyskens, Frank L.

AU - Kozawa, Susan Kurumi

AU - Liu-Smith, Feng

AU - Plascencia-Villa, Germán

AU - José-Yacamán, Miguel

AU - Jia, Shang

AU - Chang, Christopher J.

AU - Farmer, Patrick J.

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N2 - In this report, we investigate the toxicity of the ionophore thiomaltol (Htma) and Cu salts to melanoma. Divalent metal complexes of thiomaltol display toxicity against A375 melanoma cell culture resulting in a distinct apoptotic response at submicromolar concentrations, with toxicity of Cu(tma)2 > Zn(tma)2 >> Ni(tma)2. In metal-chelated media, Htma treatment shows little toxicity, but the combination with supplemental CuCl2, termed Cu/Htma treatment, results in toxicity that increases with suprastoichiometric concentrations of CuCl2 and correlates with the accumulation of intracellular copper. Electron microscopy and confocal laser scanning microscopy of Cu/Htma treated cells shows a rapid accumulation of copper within lysosomes over the course of hours, concurrent with the onset of apoptosis. A buildup of ubiquitinated proteins due to proteasome inhibition is seen on the same timescale and correlates with increases of copper without additional Htma.

AB - In this report, we investigate the toxicity of the ionophore thiomaltol (Htma) and Cu salts to melanoma. Divalent metal complexes of thiomaltol display toxicity against A375 melanoma cell culture resulting in a distinct apoptotic response at submicromolar concentrations, with toxicity of Cu(tma)2 > Zn(tma)2 >> Ni(tma)2. In metal-chelated media, Htma treatment shows little toxicity, but the combination with supplemental CuCl2, termed Cu/Htma treatment, results in toxicity that increases with suprastoichiometric concentrations of CuCl2 and correlates with the accumulation of intracellular copper. Electron microscopy and confocal laser scanning microscopy of Cu/Htma treated cells shows a rapid accumulation of copper within lysosomes over the course of hours, concurrent with the onset of apoptosis. A buildup of ubiquitinated proteins due to proteasome inhibition is seen on the same timescale and correlates with increases of copper without additional Htma.

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The ionophore thiomaltol induces rapid lysosomal accumulation of copper and apoptosis in melanoma

Abstract

Keywords

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