A prospective randomized comparative trial evaluating postoperative nutritional intervention in patients with oral cancer.

Extensive surgical treatment of oral cancer results in significant deterioration of nutritional status with concomitant increased nutrient requirements. The consequences are an elevated risk of postoperative complaints as well as morbidity and mortality. The aim of this study was to investigate an additional postoperative nutritional intervention through professional nutritional advice and nutritional supplementation in patients with oral cancer for at least six months. 62 patients with oral cancer in the department of oral and maxillofacial surgery were randomized into two groups. The intervention group received nutritional supplements, protein-rich, high-fiber diet and care by a professional nutritionist in addition to the standard treatment. The control group received only the standard treatment. Statistical analysis includes the evaluation of means and standard deviations as well as the calculation of p values with a significance level of 0.05. A deficiency of protein, albumin, vitamin D, zinc and iron was noticed in both groups immediately after surgery. Patients in the intervention group recorded significantly less weight loss (pT2 = 0.0031, pT4 = 0.0424), a more stable BMI (pT2 = 0.0496), better values for albumin (pT2 = 0.0265), vitamin A (pT3 = 0.0248, pT4 = 0.0007) and calcium (pT3 = 0.0362) during the follow-ups. The patients in the intervention group showed significantly fewer digestive problems (p = 0.0062) and muscular complaints (p = 0.0448). They showed better eating habits (p = 0.0348) and were capable of more physical activity (p = 0.0045) than patients in the control group. Patients with oral cancer can have a benefit from postoperative nutritional intervention. Early screening, appropriate care by a nutritionist and supplementation with vitamin D, zinc, calcium and protein-rich food are recommended.

Impact of dietary vitamin D on initiation and progression of oral cancer.

Calcitriol, the active metabolite of vitamin D, has been widely studied for its preventive and therapeutic activity against several cancers including oral squamous cell carcinoma (OSCC). However, the impact of dietary vitamin D supplementation on initiation and progression of OSCC is unclear. To address this gap in knowledge, we conducted preclinical trials using the 4-nitroquinoline-1-oxide 4NQO carcinogen model of oral carcinogenesis. Female C57BL/6 mice were maintained on one of three vitamin D diets [25 IU, 100 IU, 10,000 IU] and exposed to 4NQO in drinking water for 16 weeks followed by regular water for 10 weeks. Body weight measurements obtained through the study duration did not reveal any differences between the three diets. Animals on 100 IU diet showed lower incidence of high-grade dysplasia/OSCC and higher CD3 + T cells compared to animals on 25 IU and 10,000 IU diets. Serum 25OHD3 levels were highest in animals on 10,000 IU diet at week 0 prior to carcinogen exposure but showed ∼50 % reduction at week 26. Histologic evaluation revealed highest incidence of OSCC in animals maintained on 10,000 IU diet. Animals on 100 IU and 10,000 IU diets showed higher vitamin D receptor VDR and CYP24A1 immunostaining in high-grade dysplastic lesions and OSCC compared to normal tongue. Validation studies performed in a 4NQO-derived OSCC model showed that short-term treatment of animals on a 25 IU diet with calcitriol significantly inhibited tumor growth compared to controls but did not affect tumor growth in animals on reference diet 1000 IU. Collectively, our results highlight the complex dynamics between vitamin D status and oral carcinogenesis. Our observations also suggest that therapeutic benefits of short-term calcitriol treatment may be more pronounced in vitamin D deficient hosts.

Vitamin D promotes the cisplatin sensitivity of oral squamous cell carcinoma by inhibiting LCN2-modulated NF-κB pathway activation through RPS3.

Chemoresistance is a major cause of cancer progression and the mortality of cancer patients. Developing a safe strategy for enhancing chemosensitivity is a challenge for biomedical science. Recent studies have suggested that vitamin D supplementation may decrease the risk of many cancers. However, the role of vitamin D in chemotherapy remains unknown. We found that vitamin D sensitised oral cancer cells to cisplatin and partially reversed cisplatin resistance. Using RNA-seq, we discovered that lipocalin 2 (LCN2) is an important mediator. Cisplatin enhanced the expression of LCN2 by decreasing methylation at the promoter, whereas vitamin D enhanced methylation and thereby inhibited the expression of LCN2. Overexpression of LCN2 increased cell survival and cisplatin resistance both in vitro and in vivo. High LCN2 expression was positively associated with differentiation, lymph node metastasis, and T staging and predicted a poor prognosis in oral squamous cell carcinoma (OSCC) patients. LCN2 was also associated with post-chemotherapy recurrence. Moreover, we found that LCN2 promoted the activation of NF-κB by binding to ribosomal protein S3 (RPS3) and enhanced the interaction between RPS3 and p65. Our study reveals that vitamin D can enhance cisplatin chemotherapy and suggests that vitamin D should be supplied during chemotherapy; however, more follow-up clinical studies are needed.

Low dietary n-6/n-3 polyunsaturated fatty acid ratio prevents induced oral carcinoma in a hamster pouch model.

Dietary fatty acid patterns have been linked to the prevalence of certain cancers, however in oral carcinoma is limited. Thus, we investigated the chemopreventive effects of various dietary n-6 and n-3 fatty acids in a 9,10-dimethyl-1,2-benz[a]-anthracene (DMBA)- and betel quid extract (BQE) -induced hamster oral cancer model. Thirty 6-week-old adult male hamsters were housed and divided into normal, low, and high dietary n-6 and n-3 fatty acid groups under DMBA + BQE treatment for 16 weeks. The right buccal pouch of all hamsters were evaluated by tumor number, volume, burden and selected inflammatory parameters. The results indicate that the low dietary n-6/n-3 fatty acid group exhibited a significantly lower tumor number, volume, and burden than those of the other groups. Furthermore, this group had significantly lower nuclear factor-κB, proliferating cell nuclear antigen, and cyclin D1 expression in the right buccal pouch tissue. In conclusion, the lower dietary n-6/n-3 fatty acid ratio exerted chemopreventive effects in the DMBA- and BQE-induced hamster oral cancer model.

Antitumoral Effect of Hibiscus sabdariffa on Human Squamous Cell Carcinoma and Multiple Myeloma Cells.

Cancer is a leading cause of death worldwide. Despite therapeutic improvements, some cancers are still untreatable. Recently there has been an increasing interest in the use of natural substances for cancer prevention and treatment. Hibiscus sabdariffa (HS) is a plant, belonging to Malvaceae family, widespread in South Asia and Central Africa. HS extract (HSE) used in folk medicine, gained researchers' interest thanks to its antioxidant, anti-inflammatory, and chemopreventive properties. In the present study, we initially assessed HSE effect on a panel of human tumor cell lines. Then we focused our study on the following that are most sensitive to HSE action cell lines: Multiple Myeloma (MM) cells (RPMI 8226) and Oral Squamous Cell Carcinoma (OSCC) cells (SCC-25). In both RPMI 8226 and SCC-25 cells, HSE impaired cell growth, exerted a reversible cytostatic effect, and reduced cell motility and invasiveness. We evaluated the involvement of MAPKs ERK1/2 and p38 in HSE effects by using specific inhibitors, U0126 and SB203580, respectively. For both SCC-25 and RPMI 8226, HSE cytostatic effect depends on p38 activation, whereas ERK1/2 modulation is crucial for cell motility and invasiveness. Our results suggest that HSE may be a potential therapeutic agent against MM and OSCC.

Soy protein extract (SPE) exhibits differential in vitro cell proliferation effects in oral cancer and normal cell lines.

Prior research has demonstrated that specific isoflavones derived from soy may exhibit antitumor effects against many cancers, including oral cancer. Most of this prior research involved isolation and testing of individual soy components, such as genistein, daidzein, and glycitein, which exhibit cytotoxicity against cancerous cells but may also have residual cytotoxic effects on normal cells. Few studies have evaluated whole soy extract, containing a combination of these isoflavones, and other bioreactive compounds, which may function synergistically and more effectively against oral cancers. This study compared the antiproliferative effects of whole soy protein extract (SPE) on CAL 27 and SCC25 oral cancer cell lines in vitro. Administration of SPE significantly inhibited oral cancer growth and exerted these effects at lower concentrations compared with another class of flavonoids (proanthocyanidins) that were previously tested on these cell lines. This SPE-induced growth inhibition correlated with down-regulated mRNA expression in the oral cancer cell-cycle promoter ornithine decarboxylase (ODC), as well as upregulation of caspase-2 and caspase-8, initiators and effectors of apoptosis. These results suggest that SPE may represent a potential chemopreventive or chemotherapeutic option for oral cancer. Moreover, SPE may be more effective than other flavonoids currently used and may be effective at lower concentrations that approximate physiologic serum levels (0-2 µmol/l). This study may help to explain why diets rich in fruits, vegetables, and soy protein are associated with protection against development and progression of oral cancers, although further study is needed to develop specific public health recommendations for oral cancer treatment and prevention.

Dangerous nutrition? Calcium, vitamin D, and shark cartilage nutritional supplements and cancer-related hypercalcemia.

The use of nutritional supplements in the general population and in cancer patients has become very popular. These supplements are not perceived as medications and are presumed to be safe by cancer patients, who may however be at risk for hypercalcemia. We note that many of our patients who have developed symptomatic hypercalcemia were taking vitamin D, calcium, or shark cartilage supplements. We report eight cases of hypercalcemia in cancer patients seen at the Cleveland Clinic Foundation in whom these nutritional supplements may have contributed to the prevalence or severity of hypercalcemia.

Evaluation of chemoprevention of oral cancer with Spirulina fusiformis.

The blue-green microalgae Spirulina, used in daily diets of natives in Africa and America, have been found to be a rich natural source of proteins, carotenoids, and other micronutrients. Experimental studies in animal models have demonstrated an inhibitory effect of Spirulina algae on oral carcinogenesis. Studies among preschool children in India have demonstrated Spirulina fusiformis (SF) to be an effective source of dietary vitamin A. We evaluated the chemopreventive activity of SF (1 g/day for 12 mos) in reversing oral leukoplakia in pan tobacco chewers in Kerala, India. Complete regression of lesions was observed in 20 of 44 (45%) evaluable subjects supplemented with SF, as opposed to 3 of 43 (7%) in the placebo arm (p < 0.0001). When stratified by type of leukoplakia, the response was more pronounced in homogeneous lesions: complete regression was seen in 16 of 28 (57%) subjects with homogeneous leukoplakia, 2 of 8 with erythroplakia, 2 of 4 with verrucous leukoplakia, and 0 of 4 with ulcerated and nodular lesions. Within one year of discontinuing supplements, 9 of 20 (45%) complete responders with SF developed recurrent lesions. Supplementation with SF did not result in increased serum concentration of retinol or beta-carotene, nor was it associated with toxicity. This is the first human study evaluating the chemopreventive potential of SF. More studies in different settings and different populations are needed for further evaluation.