Purpose: Cancer chemoprevention is the use of natural or synthetic agents, in combination or alone, to inhibit, delay or reverse the carcinogenic process, and is an active topic of cancer research. Numerous epidemiological studies have shown the strong correlation between the consumption of fresh fruits and vegetables and a decreased cancer risk. With a food‐based approach to cancer prevention, emphasis is placed on the potential for complex mixtures of preventive agents in whole food to inhibit multiple process of carcinogenesis. In support of this approach, our laboratory conducted several preclinical animal studies that demonstrate the remarkable chemopreventive activities of black raspberries on chemically‐induced oral squamous cell carcinoma (OSCC). We have shown that an extract of lyophilized black raspberries (LBR) dramatically inhibits the in vitro proliferation of cells derived from human OSCC, suggesting that the chemoprevention of oral cancer by LBR components in vivo is possible. Survivin (BIRC5) is a member of the Inhibitor of Apoptosis (IAP) family of caspase inhibitors that direct the negative regulation of apoptosis. BIRC5 is highly expressed in most human tumors, including oral squamous cell carcinoma (OSCC), but nearly undetectable in terminally differentiated normal adult tissues. BIRC5 acts to antagonize apoptosis in tumors and to promote resistance to common apoptotic‐inducing therapies such as ionizing radiation. A series of studies examining BIRC5 in OSCC have associated increased BIRC5 expression levels with cancer progression and poor prognosis. The current study reports the LBR‐dependent modulation of BIRC5 expression in OSCCs as part of an ongoing Phase I clinical trial.
Methods: According to protocols approved by the Internal Review Board (IRB) of The Ohio State University, 24 biopsy‐confirmed OSCC patients were administered three LBR troches 4x/day (4.3g cumulative dose) between presurgical enrollment and their normally scheduled surgery. Biopsies were obtained from distant high “at‐risk normal” (N1) and tumor (T1) tissues at enrollment and following LBR exposure (N2, T2) acquired during surgical resection [exposure 2.5–34 days (mean exposure = 11.2±7.2 days)]. Pre‐validated TaqMan gene expression assays were used to assess apoptosis‐related genes for LBR‐dependent expression changes.
Results: OSCC tumor samples had significantly greater BIRC5 expression compared to the high “at‐risk normal” oral samples, both prior to (T1 vs N1, p<0.0001) and following (T2 vs N2, p=0.0115) LBR administration. In the high “at‐risk normal” oral samples, there was no significant difference in BIRC5 expression between the pre‐ and post‐LBR treatment groups (N2 vs N1, p=0.1425). There was a statistically significant decrease in tumor BIRC5 expression after LBR exposure (T2 vs T1, p=0.0199).
Conclusions: BIRC5 expression was significantly decreased in OSCC tumor tissues following short‐term exposure to LBR as part of an ongoing Phase 1 clinical trial. Consequently, down‐regulation of BIRC5 expression following administration of LBR to OSCC patients may provide mechanistic insight for future food‐based cancer risk reduction interventions.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A81.