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Combined arsenic trioxide-cisplatin treatment enhances apoptosis in oral squamous cell carcinoma cells

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Abstract

Background

Oral squamous cell carcinoma (OSCC) accounts for the majority of oral cancers. Despite recent advances in OSCC diagnostics and therapeutics, the overall survival rate still remains low. Here, we assessed the efficacy of a combinatorial arsenic trioxide (ATO) and cisplatin (CDDP) treatment in human OSCC cells.

Methods

The combinatorial effect of ATO/CDDP on the growth and apoptosis of OSCC cell lines HSC-2, HSC-3, and HSC-4 was evaluated using MTT and annexin V assays, respectively. Chou–Talalay analyses were preformed to evaluate the combinatorial effects of ATO/CDDP on the dose-reduction index (DRI). To clarify the mechanism underlying the ATO/CDDP anticancer effect, we also examined the involvement of reactive oxygen species (ROS) in ATO/CDDP-induced apoptosis.

Results

Combination index (CI) analyses revealed that a synergistic interaction of ATO and CDDP elicits a wide range of effects in HSC-2 cells, with CI values ranging from 0.78 to 0.90, where CI < 1 defines synergism. The CI values in HSC-3 and HSC-4 cells ranged from 0.34 to 0.45 and from 0.60 to 0.92, respectively. In addition, ATO/CDDP yielded favorable DRI values ranging from 1.6-fold to 7.71-fold dose reduction. Compared to mono-therapy, ATO/CDDP combinatorial therapy significantly augmented the loss of mitochondrial potential, caspase-3/7 activity and subsequent apoptosis. These changes were all abrogated by the antioxidant N-acetylcysteine.

Conclusions

This study provides the first evidence for a synergistic ATO/CDDP anticancer (apoptotic) activity in OSCC cells with a favorable DRI, thereby highlighting its potential as a combinational therapeutic regime in OSCC.

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Abbreviations

ATO:

Arsenic trioxide

BCL2:

B-cell CLL/lymphoma 2

XIAP:

X-linked inhibitor of apoptosis

CDDP:

Cisplatin

CI:

Combination index

DRI:

Dose-reduction index

OSCC:

Oral squamous cell carcinoma

ROS:

Reactive oxygen species

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Acknowledgments

This study was supported by grants of the Strategic Research Foundation Grant-aided Project for Private Universities from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan (S1101027 to S. Karnan, H. Konishi, and Y. Hosokawa), and the AIKEIKAI Foundation (to A. Ota).

Ethical standards

This research complies with the ethical guidelines of the Japanese Ministry of Health, Labour, and Welfare.

Conflict of interest

None reported.

Author information

Authors and Affiliations

  1. Department of Oral and Maxillofacial Surgery, Aichi Medical University Hospital, Nagakute, Japan

    Toshiki Nakaoka, Takayuki Ono, Akifumi Furuhashi, Yukinobu Ohmura, Yoichi Yamada & Yoshiaki Kazaoka

  2. Department of Biochemistry, Aichi Medical University School of Medicine, 1-1 Yazako karimata, Building #2, Room 362, Nagakute, Aichi, 480-1195, Japan

    Akinobu Ota, Sivasundaram Karnan, Hiroyuki Konishi & Yoshitaka Hosokawa

Authors
  1. Toshiki Nakaoka
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  2. Akinobu Ota
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Corresponding author

Correspondence to Akinobu Ota.

Additional information

Toshiki Nakaoka, Akinobu Ota, and Takayuki Ono contributed equally to this work.

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Nakaoka, T., Ota, A., Ono, T. et al. Combined arsenic trioxide-cisplatin treatment enhances apoptosis in oral squamous cell carcinoma cells. Cell Oncol. 37, 119–129 (2014). https://doi.org/10.1007/s13402-014-0167-7

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