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Combinatorial action of the HDAC inhibitor trichostatin A and etoposide induces caspase-mediated AIF-dependent apoptotic cell death in non-small cell lung carcinoma cells

Oncogene volume 27, pages 3134–3144 (2008)Cite this article

Abstract

Commonly used regimens in cancer therapy rely on the induction of apoptotic cell death, and drug resistance can be attributed, at least in part, to a disabled apoptotic program. Non-small cell lung carcinomas (NSCLC), exhibit an intrinsic resistance to chemotherapy. Here, we show that co-treatment with etoposide (VP16) and the pan-histone deacetylase (HDAC) inhibitor trichostatin A (TSA), but not valproic acid (VPA), induced apoptotic cell death in drug-resistant NSCLC cells. Co-treatment, but not single treatment, with VP16 and TSA induced apoptosis in a caspase-dependent manner accompanied by a crucial decrease in Bcl-xL expression allowing Bax activation and subsequent initiation of the apoptosis inducing factor (AIF)-dependent death pathway. Importantly, AIF proved to be required for the effects of TSA/VP16 as RNA knockdown of AIF resulted in a complete abolishment of TSA/VP16-induced apoptotic cell death in drug-resistant NSCLC cells. Our results thus provide evidence for the requirement of both caspase-dependent and caspase-independent apoptotic pathways in TSA/VP16-mediated death of drug-resistant NSCLC cells, and extend previous suggestions that HDAC inhibitors in combination with conventional chemotherapeutic drugs could be valuable in the treatment of NSCLC cancer and other malignancies in which Bcl-xL is overexpressed.

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Abbreviations

AIF:

apoptosis inducing factor

CFP:

cyan fluorescent protein

Cyt c:

cytochrome c

FACS:

fluorescence-activated cell sorting

G3PDH:

glyceraldehyde-3-phosphate dehydrogenase

GFP:

green fluorescent protein

HDAC:

histone deacetylase

HDACi:

HDAC inhibitor

ΔΨm:

mitochondrial transmembrane potential

NSCLC:

non-small cell lung carcinoma

PARP:

poly(ADP-ribose)polymerase

PFGE:

pulse-field gel electrophoresis

STS:

staurosporine

TSA:

trichostatin A

VPA:

valproic acid/valproate

VP16:

vepesid/etoposide

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Acknowledgements

We thank Dr U Moll (Stony Brook University) for providing us with Bcl-xL DNA construct and Dr T Perlmann and Dr S Orrenius for permanent support. This work was supported by grants from the Swedish Research Council, the Swedish Cancer Society, the Åke Wiberg Foundation, the Swedish Medical Society, Karolinska Institutet Foundations (KI Cancer) (BJ and OH), the Swedish Children's Cancer Foundation, the Magn. Bergvall Foundation, the Lars Hierta Foundation, the Jeansson Foundation and the Åhlén Foundation (OH).

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Authors and Affiliations

  1. Division of Toxicology and Neurotoxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

    N Hajji, P Vlachos, U Nyman & B Joseph

  2. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden

    K Wallenborg & O Hermanson

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  1. N Hajji
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Correspondence to B Joseph.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Hajji, N., Wallenborg, K., Vlachos, P. et al. Combinatorial action of the HDAC inhibitor trichostatin A and etoposide induces caspase-mediated AIF-dependent apoptotic cell death in non-small cell lung carcinoma cells. Oncogene 27, 3134–3144 (2008). https://doi.org/10.1038/sj.onc.1210976

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