Anticancer Activity of Apaziquone in Oral Cancer Cells and Xenograft Model: Implications for Oral Cancer Therapy

Gunjan Srivastava; Raj Thani Somasundaram; Paul G Walfish; Ranju Ralhan

doi:10.1371/journal.pone.0133735

Anticancer Activity of Apaziquone in Oral Cancer Cells and Xenograft Model: Implications for Oral Cancer Therapy

PLoS One. 2015 Jul 24;10(7):e0133735. doi: 10.1371/journal.pone.0133735. eCollection 2015.

Authors

Gunjan Srivastava¹, Raj Thani Somasundaram¹, Paul G Walfish², Ranju Ralhan³

Affiliations

¹ Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Mount Sinai Hospital, Toronto, Canada.
² Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Mount Sinai Hospital, Toronto, Canada; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada; Joseph and Mildred Sonshine Family Centre for Head and Neck Diseases, Department of Otolaryngology-Head and Neck Surgery, Mount Sinai Hospital, Toronto, Canada; Department of Medicine, Endocrine Division, Mount Sinai Hospital and University of Toronto, Toronto, Canada; Department of Otolaryngology-Head and Neck Surgery, University of Toronto, Toronto, Canada.
³ Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Mount Sinai Hospital, Toronto, Canada; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada; Joseph and Mildred Sonshine Family Centre for Head and Neck Diseases, Department of Otolaryngology-Head and Neck Surgery, Mount Sinai Hospital, Toronto, Canada; Department of Otolaryngology-Head and Neck Surgery, University of Toronto, Toronto, Canada.

Abstract

Oral squamous cell carcinoma (OSCC) patients diagnosed in late stages have limited chemotherapeutic options underscoring the great need for development of new anticancer agents for more effective disease management. We aimed to investigate the anticancer potential of Apaziquone, [EOquin, USAN, E09, 3-hydroxy-5- aziridinyl-1-methyl-2(1H-indole-4,7-dione)-prop-β-en-α-ol], a pro-drug belonging to a class of anti-cancer agents called bioreductive alkylating agents, for OSCC. Apaziquone treatment inhibited cell proliferation and induced apoptosis in OSCC cells in vitro. Apaziquone treated OSCC cells showed increased activation of Caspase 9 and Caspase 3, and Poly (ADP ribose) polymerase (PARP) cleavage suggesting induction of apoptosis by apaziquone in oral cancer cells. Importantly, apaziquone treatment significantly reduced oral tumor xenograft volume in immunocompromised NOD/SCID/Crl mice without causing apparent toxicity to normal tissues. In conclusion, our in vitro and in vivo studies identified and demonstrated the pre-clinical efficacy of Apaziquone, as a potential novel anti-cancer therapeutic candidate for oral cancer management.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Annexin A5 / metabolism
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Aziridines / administration & dosage
Aziridines / pharmacology*
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Disease Models, Animal
Dose-Response Relationship, Drug
Humans
Indolequinones / administration & dosage
Indolequinones / pharmacology*
Mice
Mouth Neoplasms / drug therapy
Mouth Neoplasms / metabolism
Mouth Neoplasms / pathology*
Tumor Burden
Xenograft Model Antitumor Assays

Substances

Annexin A5
Antineoplastic Agents
Aziridines
Indolequinones
apaziquone

Grants and funding

The financial support of this work was provided by Spectrum Pharmaceuticals Inc. (Irvine, CA). The funders approved the study design, but had no role in data collection and analysis, decision to publish, or preparation of the manuscript. The authors gratefully acknowledge the Canadian Institutes of Health Research for Chair in Advanced Cancer Diagnostics (RR), and Alex and Simona Shnaider Chair in Thyroid Cancer (PGW).