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.
Highlights
Oral squamous cell carcinoma (OSCC) comprise a large proportion of head and neck cancer accounting for an estimated 263,000 new cases and about 127,000 deaths worldwide each year [1]
Early-stage (I and II) OSCC patients are treated with surgery and/or radiotherapy, and have five-year survival rates of 70%– 90% [2,3,4]
With increasing dose of Apaziquone expression of the full length Caspase 9 protein decreased and the cleaved Caspase 9 increased, while the expression of cleaved Poly (ADP ribose) polymerase (PARP) and cleaved Caspase 3 increased. (Fig 2A and S1 Fig) and similar effect of Apaziquone was observed in SCC4 cells on these proteins (Fig 2B and S1 Fig), confirming the induction of apoptosis by apaziquone treatment in both oral cancer cell lines
Summary
Oral squamous cell carcinoma (OSCC) comprise a large proportion of head and neck cancer accounting for an estimated 263,000 new cases and about 127,000 deaths worldwide each year [1]. Early-stage (I and II) OSCC patients are treated with surgery and/or radiotherapy, and have five-year survival rates of 70%– 90% [2,3,4]. Two-thirds of OSCC patients suffer from loco-regional advanced disease (stages III and IV) at the time of diagnosis. There exists inadequate data from randomized clinical trials to define an optimal strategy for patients with stages III and IV OSCC. Patients with advanced or recurrent disease have limited treatment.
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