Dysplasia is a histologic precursor of esophageal squamous cell carcinoma (SCC). We previously showed that dietary freeze-dried, or lyophilized, strawberry powder inhibits N-nitrosomethylbenzylamine-induced SCC in the rat esophagus. On the basis of this observation, we conducted a randomized (noncomparative) phase II trial in China to investigate the effects of two doses of freeze-dried strawberries in patients with esophageal dysplastic lesions in a high-risk area for esophageal cancer. We randomly assigned 75 patients identified by endoscopy to have dysplastic esophageal premalignant lesions to receive freeze-dried strawberry powder at either 30 g/d (37 patients) or 60 g/d (38 patients) for six months; the powder was mixed with water and drunk. After six months, we assessed the changes in histologic grade of these lesions (primary endpoint) in a blinded fashion. The dose of 30 g/d, did not significantly affect histology or any other measured parameter. The dose of 60 g/d, however, reduced the histologic grade of dysplastic premalignant lesions in 29 (80.6%) of the 36 patients at this dose who were evaluated for histology (P < 0.0001). The strawberry powder was well tolerated, with no toxic effects or serious adverse events. Strawberries (60 g/d) also reduced protein expression levels of inducible nitric oxide synthase (iNOS) by 79.5% (P < 0.001), cyclooxygenase-2 (COX-2) by 62.9% (P < 0.001), phospho-nuclear factor kappa B (NFκB)-p65 (pNFκB-p65) by 62.6% (P < 0.001), and phospho-S6 (pS6) by 73.2% (P < 0.001). Freeze-dried strawberries (60 g/d) also significantly inhibited the Ki-67 labeling index by 37.9% (P = 0.023). Our present results indicate the potential of freeze-dried strawberry powder for preventing human esophageal cancer, supporting further clinical testing of this natural agent in this setting. Cancer Prev Res; 5(1); 41–50. ©2011 AACR.

Angiogenesis, the formation of new blood vessels, is critical to tumor growth and metastasis. Vascular endothelial growth factor (VEGF), an important angiogenic activator, is essential for angiogenesis. Our laboratory has used a rodent model of human esophageal squamous cell carcinoma (ESCC) to identify putative chemopreventive agents for this disease and determine their mechanisms of action. We reported that dietary black raspberry powder (BRB) inhibits N -nitrosomethylbenzylamine (NMBA)-induced tumor development in the rat esophagus by inhibiting the formation of DNA adducts and reducing the proliferation rate of preneoplastic cells. On a molecular level, BRB downregulates the expression of c-Jun, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). In this study we analyzed the effect of BRB on angiogenesis. VEGF expression was determined by real-time RT–PCR and immunohistochemical analysis of microvessel density (MVD). BRB significantly suppressed VEGF-C expression from a 2.38 (± 0.34)-fold increase in animals treated with NMBA alone to a 1.08 (± 0.22)-fold increase in animals treated with NMBA plus BRB ( P < 0.005). The MVD of esophagus was decreased from 53.7 ± 5.6 vessels/cm in animals treated with NMBA alone to 22.6 ± 2.6 vessels/cm in animals treated with NMBA plus BRB ( P < 0.0001). Our data also suggest that downregulation of VEGF is correlated with suppression of COX-2 ( r² = 0.86, P < 0.001) and iNOS ( r² = 0.81, P < 0.005). As high vascularity is a risk factor for metastasis and tumor recurrence, BRB may have cancer therapeutic effects in human esophageal cancer.

The intricate role of inducible nitric oxide synthase (iNOS) in cancer pathophysiology has garnered significant attention, highlighting the complex interplay between tumorigenesis, immune response, and cellular metabolism. As an enzyme responsible for producing nitric oxide (NO) in response to inflammatory stimuli. iNOS is implicated in various aspects of cancer development, including DNA damage, angiogenesis, and evasion of apoptosis. This review synthesizes the current findings from both preclinical and clinical studies on iNOS across different cancer types, reflecting the variability depending on cellular context and tumor microenvironment. We explore the molecular mechanisms by which iNOS modulates cancer cell growth, survival, and metastasis, emphasizing its impact on immune surveillance and response to treatment. Additionally, the potential of targeting iNOS as a therapeutic strategy in cancer treatment is examined. By integrating insights from recent advances, this review aims to elucidate the significant role of iNOS in cancer and pave the way for novel diagnostic and therapeutic approaches.

Human and experimental colon carcinogenesis are enhanced by a pro-inflammatory microenvironment. Pharmacologically driven chemopreventive agents and dietary variables are hypothesized to have future roles in the prevention of colon cancer by targeting these processes. The current study was designed to determine the ability of dietary lyophilized strawberries to inhibit inflammation-promoted colon carcinogenesis in a preclinical animal model. Mice were given a single i.p. injection of azoxymethane (10 mg kg⁻¹ body weight). One week after injection, mice were administered 2% (w/v) dextran sodium sulfate in drinking water for seven days and then an experimental diet containing chemically characterized lyophilized strawberries for the duration of the bioassay. Mice fed control diet, or experimental diet containing 2.5%, 5.0% or 10.0% strawberries displayed tumor incidence of 100%, 64%, 75% and 44%, respectively (p < 0.05). The mechanistic studies demonstrate that strawberries reduced expression of proinflammatory mediators, suppressed nitrosative stress and decreased phosphorylation of phosphatidylinositol 3-kinase, Akt, extracellular signal-regulated kinase and nuclear factor kappa B. In conclusion, strawberries target proinflammatory mediators and oncogenic signaling for the preventive efficacies against colon carcinogenesis in mice. This works supports future development of fully characterized and precisely controlled functional foods for testing in human clinical trials for this disease.

Colorectal cancer (CRC) is still a big health burden worldwide. Nutrition and dietary factors are known to affect colorectal cancer development and prognosis. The protective roles of diets rich in fruits and vegetables have been previously reported to contain high levels of cancer-fighting phytochemicals. Anthocyanins are the most abundant flavonoid compounds that are responsible for the bright colors of most blue, purple, and red fruits and vegetables, and have been shown to contribute to the protective effects of fruits and vegetables against cancer and other chronic diseases. Berries and grapes are the most common anthocyanin-rich fruits with antitumor effects. The antitumor effects of anthocyanins are determined by their structures and bioavailability as well as how they are metabolized. In this review, we aimed to discuss the preventive as well as therapeutic potentials of anthocyanins in CRC. We summarized the antitumor effects of anthocyanins and the mechanisms of action. We also discussed the potential pharmaceutical application of anthocyanins in practice.