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Regulation of apoptosis in human melanoma and neuroblastoma cells by statins, sodium arsenite and TRAIL: a role of combined treatment versus monotherapy

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Abstract

Treatment of melanoma cells by sodium arsenite or statins (simvastatin and lovastatin) dramatically modified activities of the main cell signaling pathways resulting in the induction of heme oxygenase-1 (HO-1) and in a downregulation of cyclooxygenase-2 (COX-2) protein levels. Through heme degradation and the production of carbon monoxide and biliverdin, HO-1 plays a protective role in different scenario of oxidative stress followed by mitochondrial apoptosis. Both sodium arsenite and statins could be efficient inducers of apoptosis in some melanoma cell lines, but often exhibited only modest proapoptotic activity in others, due to numerous protective mechanisms. We demonstrated in the present study that treatment by sodium arsenite or statins with an additional inhibition of HO-1 expression (or activation) caused a substantial upregulation of apoptosis in melanoma cells. Sodium arsenite- or statin-induced apoptosis was independent of BRAF status (wild type versus V600E) in melanoma lines. Monotreatment required high doses of statins (20–40 μM) for effective induction of apoptosis. As an alternative approach, pretreatment of melanoma cells with statin at decreased doses (5–20 μM) dramatically enhanced TRAIL-induced apoptosis, due to suppression of the NF-κB and STAT3-transcriptional targets (including COX-2) and downregulation of cFLIP-L (a caspase-8 inhibitor) protein levels. Furthermore, combined treatment with sodium arsenite and TRAIL or simvastatin and TRAIL efficiently induced apoptotic commitment in human neuroblastoma cells. In summary, our findings on enhancing effects of combined treatment of cancer cells using statin and TRAIL provide the rationale for further preclinical evaluation.

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Abbreviations

COX-2:

Cyclooxygenase-2

DR4:

Death receptor-4

DR5:

Death receptor-5

ERK:

Extracellular signal-regulated kinase

FACS:

Fluorescence-activated cell sorter

HO-1:

Heme oxygenase-1

IETD:

N-acetyl-Ile-Glu-Thr-Asp-CHO (aldehyde)

IL1β:

Interleukin1β

IL6:

Interleukin-6

IκB:

Inhibitor of NF-κB

IKK:

Inhibitor of nuclear factor kappa B kinase

LEHD:

N-acetyl-Leu-Glu-His-Asp-CHO (aldehyde)

MAPK:

Mitogen-activated protein kinase

MFI:

Medium fluorescence intensity

NF-κB:

Nuclear factor kappa B

PI:

Propidium iodide

PI3K:

Phosphoinositide 3-kinase

PARP-1:

Poly (ADP-ribose) polymerase-1

PTGS2:

Prostaglandin-endoperoxide synthase 2

ROS:

Reactive oxygen species

TNFα:

Tumor necrosis factor alpha

TRAIL:

TNF-related apoptosis inducing ligand

TRAIL-R:

TRAIL-Receptor

zVAD:

Carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone

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Acknowledgments

We would like to thank Dr. S. Snyder for HO-1 Null fibroblasts, Drs. M. Herlyn and Z. Ronai for melanoma cell lines, Dr. Y. Chai for ELISA detections of cytokines, Drs. H. B. Lieberman and J. A. Meador for a critical reading of the manuscript and discussion. This research was supported by Superfund Grant ES 10349.

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No potential conflicts of interest were disclosed.

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  1. Department of Radiation Oncology, Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA

    Vladimir N. Ivanov & Tom K. Hei

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  1. Vladimir N. Ivanov
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Correspondence to Vladimir N. Ivanov.

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Ivanov, V.N., Hei, T.K. Regulation of apoptosis in human melanoma and neuroblastoma cells by statins, sodium arsenite and TRAIL: a role of combined treatment versus monotherapy. Apoptosis 16, 1268–1284 (2011). https://doi.org/10.1007/s10495-011-0649-2

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