Chemoprevention of oral cancer in animal models, and effect on leukoplakias in human patients with ZengShengPing, a mixture of medicinal herbs

Summary

ZengShengPing (ZSP), a mixture of six medicinal herbs, has been reported to prevent esophageal squamous cell carcinoma (SCC) in human patients with dysplasia. This study was designed to investigate the chemopreventive effects of ZSP on oral cancer in animal models and human patients. In the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster cheek pouch model, ZSP (6 g/kg BW/day by gavage for 10 weeks) significantly reduced the number of visible tumor, the tumor volume, and the incidence of SCC (P < 0.01). Two biomarkers associated with cell proliferation, silver stained nucleolar organizer region (AgNOR) and proliferating cell nuclear antigen (PCNA)-labeling index, were also significantly suppressed by ZSP treatment (P < 0.01). In the 4-nitroquinoline 1-oxide (4NQO)-induced oro-esophageal cancer model in mice, ZSP (10% in diet) also significantly reduced the incidence of tongue SCC from 55.2% (16/29) to 22.2% (6/27) (P < 0.05), and slightly reduced the incidence of esophageal SCC from 34.5% (10/29) to 22.2% (6/27). Furthermore, in a randomized clinical trial on patients with oral leukoplakia, ZSP (4 tablets, 3 times per day for 8–12 months) reduced the size of oral lesion in 67.8% (40/59) patients, whereas the placebo was effective in 17% (9/53) patients (P < 0.01). Such an effect was associated with significant decrease of AgNOR and PCNA-labeling index. In summary, our studies have demonstrated the chemopreventive effects of ZSP on two animal models of oral cancer, and human patients with oral leukoplakia.

Introduction

Oro-esophageal squamous cell carcinoma (SCC) is a commonly seen cancer worldwide, and is mainly prevalent in developing countries. Despite significant improvements in early diagnosis and treatment, these cancers still have a high rate of mortality worldwide.¹ Hence, it is important to understand its pathogenesis and to develop novel and effective chemopreventive strategies.

ZengShengPing^® (ZSP) is a herbal mixture composed of six herbs, Sophra tonkinensis, Polygonum bistorta, Prunella vulgaris, Sonchus brachyotus, Dictamnus dasycarpus, and Dioscorea bulbifera. ZSP tablets are made by mixing the water extract of S. tonkinensis (18–24%, w/w), P. bistorta (17–21%), P. vulgaris (18–25%), S. brachyotus (17–23%), and D. bulbifera (3–6%), with the powder of D. dasycarpus (8–12%). Preclinical studies have shown that ZSP inhibited inflammation and inflammation-associated carcinogenesis in animal models. Clinical trials in China from later 1970s to early 1990s have confirmed that oral intake of ZSP had significant chemopreventive effects on esophageal SCC in patients with high-grade dysplasia (Table 1). Based on these studies, ZSP tablet is now widely prescribed to patients with dysplasia for chemoprevention of esophageal SCC. Potential use of ZSP for other cancers is also under investigation. In a recent clinical trial on smokers with bronchial dysplasia in North America, treatment with ZSP for 6 months induced a complete regression rate of 64% as compared to 26% in the placebo group.² A Phase II clinical trial on ZSP (ACAPHA^® in North America) is currently ongoing (www.clinicaltrials.gov).

Since oral SCC is very similar to esophageal SCC in etiology, histopathology and molecular mechanism, it is likely that ZSP may be effective for oral cancer chemoprevention. However, the chemopreventive effects of ZSP on oral cancer have not yet been systematically studied. In the present study, we examined the chemopreventive effects of ZSP in two animal models and a short-term clinical trial. These animal models have been well characterized and are commonly used for chemoprevention research on oral cancer.[3], [4]