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Forkhead box protein M1 (FOXM1) is an oncoprotein that is involved in cell proliferation, differentiation and aging, and overexpression of FOXM1 is thought to be associated with the development and progression of various types of cancer. The expression of FOXM1 was retrospectively examined in tumor tissues taken from 56 oral squamous cell carcinoma (OSCC) patients by immunohistochemical staining. All of these patients received docetaxel (Doc)-containing regimens as treatments against OSCC. The association between FOXM1 expression and the clinicopathological characteristics and prognosis of these patients was then examined. FOXM1 was expressed in the nucleus and cytoplasm of OSCC tissues samples. There was a significant association between FOXM1 expression in tumor tissues and N classification (P=0.0395), stage (P=0.004), therapeutic efficacy (P=0.0113) and outcome (P=0.0134) of patients. However, FOXM1 expression had no association with patients' sex, age or T classification. Additionally, high expression of FOXM1 in tumor cells was associated with a shorter overall survival (P=0.0257) of patients. Multivariate analysis also revealed that elevated expression of FOXM1 was a predictor of patients' poor survival (P=0.0327). The results suggested that high expression of FOXM1 in OSCC tumors may result in reduced therapeutic effects and poor clinical outcomes of patients receiving Doc-based treatment regimens. [ABSTRACT FROM AUTHOR]

Oral mucositis is a common adverse effect of cancer treatment that can increase the risk for local and systemic infection. This prospective study was designed to evaluate the preventive effects of an amino-acid-rich elemental diet (ED), Elental®, on radiotherapy- or chemoradiotherapy-induced mucositis in oral squamous cell carcinoma (OSCC) patients. Fifty patients were enrolled in this prospective study, who had received radiation (60–70 Gy) with/without chemotherapy [S-1, UFT, cisplatin (CDDP), docetaxel (DOC) plus CDDP, or Cetuximab]. The Elental® group (25 patients) had received Elental® during treatment, and the control group (25 patients) had not. Multivariate logistic regression analysis was used to identify the factors related to abatement of oral mucositis. A comparison of the rates of completion of chemoradiation treatments as well as the nutritional or inflammatory status between Elental® and control groups was performed. Multivariate analysis indicated that most of the patients who received Elental® suffered from a lower degree of mucositis and showed significantly improved rate of completion of chemoradiation (no interruption) compared to the control group. There was a significant difference between the Elental® group and the control group in terms of the mean change of C-reactive protein (CRP) levels in blood serum; however, there was no significant difference in terms of a mean change of body weight and total protein level in blood serum before and after chemoradiation. Our study shows that the Elental® elemental diet could be useful for the treatment of oral mucositis induced by chemoradiation. Elental® might also promote improved completion rates of chemoradiotherapy in OSCC patients. [ABSTRACT FROM AUTHOR]

Mucositis and dermatitis induced by anticancer agents are common complications of anticancer therapies. In this study, we evaluated the efficacy of Elental (Ajinomoto Pharmaceutical Ltd, Tokyo, Japan), an elemental diet with glutamine in the treatment of 5-fluorouracil (5-FU)-induced oral mucositis and dermatitis in vivo and tried to clarify the underlying mechanisms of its action. Oral mucositis and dermatitis was induced through a combination of 5-FU treatment and mild abrasion of the cheek pouch in hamsters and the dorsal skin in nude mice respectively. These animals received saline, dextrin or Elental suspension (18 kcal/100 g) by a gastric tube daily until sacrifice. Elental reduced oral mucositis and dermatitis more effectively than dextrin in the animal model. Moreover, growth facilitating effects of Elental on HaCaT cells were examined in vitro. MTT assay, wound healing assay, and migration assay revealed that Elental could enhance the growth, invasion, and migration ability of HaCaT. ELISA and Western blotting showed upregulated FGF2 in Elental-treated HaCaT. These findings suggest that Elental is effective for the treatment of mucositis and dermatitis, and may accelerate mucosal and skin recovery through FGF2 induction and reepithelization. [ABSTRACT FROM AUTHOR]

Background: The cancer stem cells (CSCs), a small subpopulation of cells in tumor are responsible for the tumor initiation, growth, recurrence and metastasis of cancer, as well as resistance of cancers to drugs or radiotherapy. CSCs are an important target for the development of novel strategies in cancer treatment. However, CSCs-targeted new anti-cancer drug discovery is currently hindered by the lack of easy and reliable methods for isolating, collecting and maintaining sufficient number of CSCs. Here, we examined whether introduction of defined reprogramming factors (Oct4, shp53, Sox2, Klf4, l-Myc and Lin28) into HSC2 tongue cancer cells could transform the HSC2 into HSC2 with CSCs properties.Methods: We introduced the defined reprogramming factors into HSC2 tongue cancer cells via episomal vectors by electroporation method to generate transfectant cells. We investigated the malignant properties of the transfectant cells by cell proliferation assay, migration assay, wound healing assay, sphere formation assay, chemosensitivity and radiosensitivity assay in vitro; and also examined the tumorigenic potential of the transfectants in vivo.Results: The transfectant cells (HSC2/hOCT3/4-shp53-F, HSC2/hSK, HSC2/hUL, HSC2/hOCT3/4-shp53-F + hSK, HSC2/hOCT3/4-shp53-F + hUL, HSC2/hSK + hUL, HSC2/hOCT3/4-shp53-F + hSK + hUL) displayed a malignant phenotype in culture and form tumors on the back of nude mice more efficiently than parental HSC2 and control HSC2/EGFP transfectant cells. They exhibited increased resistance to chemotherapeutic agents; 5-fluorouracil, cisplatin, docetaxel, trifluorothymidine, zoledronic acid, cetuximab, bortezomib and radiation when compared with HSC2 and HSC2/EGFP. Among all the transfected cells, HSC2/hOCT3/4-shp53-F + hSK + hUL cell containing all of the reprogramming factors showed the most aggressive and malignant properties and presented the highest number of spheres in the culture medium containing human recombinant fibroblast Growth Factor-2 (FGF-2) and epidermal Growth Factor (EGF).Conclusion: These findings suggest that artificial cancer stem cells obtained by the induction of cellular reprogramming may be useful for investigating the acquisition of potential malignancy as well as screening the CSCs-targeting drugs. [ABSTRACT FROM AUTHOR]

Background/aim: This study aimed to identify the most useful components of Elental ® in the treatment of 5-fluorouracil (FU)-induced mucositis and salivary gland atrophy in mice., Materials and Methods: Mice (except the control group) were intraperitoneally injected with 5-FU. The mice received saline (control group and 5-FU group), dextrin (Dextrin group), amino acids (17AA group), or Elental ® (Elental ® group)., Results: The volume and weight of salivary glands was higher in 17AA and Elental ® groups compared to 5-FU group. The number of mucous glands was higher, whereas the number of damaged granular ductal epithelial cells was lower in the salivary glands of all groups except the 5-FU group. Salivation was also decreased in the 5-FU group compared to the other groups., Conclusion: Amino acids could be the most effective components of Elental ® for protecting mouse salivary glands from 5-FU-induced atrophic changes, and might be useful in the treatment of oral mucositis in cancer patients., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Oral mucositis is a common adverse effect of cancer treatment that can increase the risk for local and systemic infection. This prospective study was designed to evaluate the preventive effects of an amino-acid-rich elemental diet (ED), Elental ® , on radiotherapy- or chemoradiotherapy-induced mucositis in oral squamous cell carcinoma (OSCC) patients. Fifty patients were enrolled in this prospective study, who had received radiation (60-70 Gy) with/without chemotherapy [S-1, UFT, cisplatin (CDDP), docetaxel (DOC) plus CDDP, or Cetuximab]. The Elental ® group (25 patients) had received Elental ® during treatment, and the control group (25 patients) had not. Multivariate logistic regression analysis was used to identify the factors related to abatement of oral mucositis. A comparison of the rates of completion of chemoradiation treatments as well as the nutritional or inflammatory status between Elental ® and control groups was performed. Multivariate analysis indicated that most of the patients who received Elental ® suffered from a lower degree of mucositis and showed significantly improved rate of completion of chemoradiation (no interruption) compared to the control group. There was a significant difference between the Elental ® group and the control group in terms of the mean change of C-reactive protein (CRP) levels in blood serum; however, there was no significant difference in terms of a mean change of body weight and total protein level in blood serum before and after chemoradiation. Our study shows that the Elental ® elemental diet could be useful for the treatment of oral mucositis induced by chemoradiation. Elental ® might also promote improved completion rates of chemoradiotherapy in OSCC patients.

Cepharanthine is a biscoclaurine alkaloid extracted from Stephania cepharantha Hayata, which is widely used for the treatment of many acute and chronic diseases, and can exert antitumor effects on several human cancer cell lines. However, little is known about the detailed mechanisms of the antitumor activity of Cepharanthine. In the present study, we determined whether Cepharanthine could suppress angiogenesis and growth of human oral squamous cell carcinoma (OSCC) cells in vitro and in vivo. Cepharanthine significantly inhibited expression of two major pro-angiogenic molecules, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), in cultured cells and in cells implanted into the subcutaneous tissue of nude mice. Also, Cepharanthine inhibited the nuclear factor-kappaB (NF-kappaB) activity in human OSCC cells in vitro and in vivo. The decreased expression of VEGF and IL-8 correlated with decreased tumor cell growth and decreased vascularization in vitro and in vivo. These findings suggest that Cepharanthine can suppress angiogenesis and growth of OSCC cells by inhibiting expression of VEGF and IL-8 involved in the blockade of NF-kappaB activity.

Background: Chemotherapy has shown little antitumor activity against advanced oral squamous cell carcinoma (OSCC) patients. Therefore, there is an urgent need to develop more effective therapeutic methods for patients with advanced OSCC. Cepharanthine is a biscoclaurine alkaloid extracted from Stephania cepharantha Hayata, which is widely used for the treatment of many acute and chronic diseases, and can exert antitumor effects on several human cancer cells. S-1 is a new oral antineoplastic agent that can induce apoptosis in various types of cancer cells, including OSCC. Hence combined treatment of cancer cells with cepharanthine and S-1 might exert dramatic antitumor effects on OSCC cells., Materials and Methods: In this study, the response of human OSCC cells to cepharanthine alone and in combination with S-1 was examined using nude mouse xenograft models. S-1 (10 mg/kg/day, 5 times/week) was administered orally and cepharanthine (20 mg/kg, 5 times/week) was injected into peritumoral tissue for three weeks. Apoptotic cells were detected by a TUNEL method. The protein expression of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and orotate phosphoribosyl transferase (OPRT) were assessed using immunohistochemistry; their gene expression was determined using microdissection and RT-PCR, and their protein levels using ELISA., Results: Combined therapy of cepharanthine and S-1 exerted antitumor effects on human OSCC xenografts markedly and significantly induced apoptotic cells in tumors treated with cepharanthine plus S-1. Immunohistochemistry showed that the expressions of TS and DPD were down-regulated, and that OPRT expression was up-regulated in tumors treated with cepharanthine plus S-1. In the same way, microdissection and RT-PCR revealed that the expression of TS and DPD mRNA was down-regulated and that expression of OPRT mRNA was up-regulated in tumors administered the combined treatment. Moreover, ELISA indicated that the protein levels of TS and DPD were down-regulated, and that OPRT was up-regulated in tumors treated with the combined therapy. During the experimental period, no loss of body weight was observed in mice treated with the combined therapy., Conclusion: These findings demonstrate that the combination of cepharanthine and S-1 is effective against OSCC and has the potential of being a new therapeutic tool for future treatment of these tumors.

In the present study, we examined the appropriate schedule of S-1 medication in the combination with radiation by investigating the safety, the clinical efficacy, and antitumor effects on tumors in nude mice. In the patients with oral squamous cell carcinoma (OSCC), S-1 was given orally according to a 4-week application followed by 2-week rest regimen (4-week regimen), or a 2-week application followed by a 1-week rest regimen (2-week regimen). Radiation was given (2 Gy/day; 5 days/week) for a total of 60 Gy. In nude mouse models, human oral cancer cell lines were used as subcutaneous xenografts in nude mice. The mice were treated by S-1 (10 mg/kg) and radiation (1 Gy) with a 4-week regimen or a 2-week regimen. Apoptotic cells were detected by TUNEL method. In the patients with OSCC, the response rate with the 4-week regimen was 100% and the response rate with the 2-week regimen was 92.3%. However, a high frequency of adverse effect was found in the 4-week regimen when compared to the 2-week regimen. Grade 3 toxicity of leukopenia, neutropenia and stomatitis were seen in 3 cases, grade 3 toxicity of anorexia and nausea were seen in 2 cases, and grade 3 toxicity of decrease of hemoglobin level, heartburn/dyspepsia and increase of bilirubin level were seen in a case of the 4-week regimen. On the other hand, grade 3 toxicity of stomatitis, anorexia, nausea, heartburn/dyspepsia and increase of bilirubin level were seen in a case of the 2-week regimen. In nude mouse models, the 2-week regimen was more effective than the 4-week regimen. In addition, significant increase in the percentage of apoptotic cells was observed in the tumors treated with the 4-week regimen when compared with the tumors treated with the 2-week regimen. No loss of body weight was observed in mice treated with the 2-week regimen during the experimental period. These results suggested that the 2-week regimen might reduce adverse effects, and enhance therapeutic effects compared to the 4-week regimen. Briefly, this 2-week regimen may be a useful concurrent chemo-radiotherapy improving the quality of life (QOL) of patients with OSCC.

Background: Chemotherapy has shown little antitumor activity against advanced oral squamous cell carcinoma (OSCC) patients. Therefore, there is an urgent need to develop more effective therapeutic methods for patients with advanced OSCC. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor ligand family that selectively induces apoptosis of cancer cells. S-1 is a new oral antineoplastic agent that can induce apoptosis in various types of cancer cells, including OSCC. Hence, combined treatment of cancer cells with TRAIL and S-1 might exert dramatic antitumor effects on OSCC cells., Materials and Methods: In this study, the response of human OSCC cells to TRAIL alone and in combination with S-1 was examined using nude mouse xenograft models. S-1 (10 mg/kg/day, 5 times/week) was administered orally and TRAIL (1 mg/kg, 5 times/week) was injected into peritumoral tissue for three weeks. Apoptotic cells were detected by a TUNEL method. The protein expression of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and orotate phosphoribosyl transferase (OPRT) were assessed using immunohistochemistry; their gene expression was determined using microdissection and RT-PCR, and their protein levels using ELISA., Results: Combined therapy of TRAIL and S-1 exerted antitumor effects on human OSCC xenografts markedly and significantly induced apoptotic cells in tumors treated with TRAIL plus S-1. Immunohistochemistry showed that the expressions of TS and DPD were down-regulated, and that OPRT expression was up-regulated in tumors treated with TRAIL plus S-1. In the same way, microdissection and RT-PCR revealed that the expression of TS and DPD mRNA was down-regulated and that expression of OPRT mRNA was up-regulated in tumors administered the combined treatment. Moreover, ELISA indicated that the protein levels of TS and DPD were down-regulated, and that OPRT was up-regulated in tumors treated with the combined therapy. During the experimental period, no loss of body weight was observed in mice treated with the combined therapy., Conclusion: These findings demonstrate that the combination of TRAIL and S-1 is effective against OSCC and has the potential of being a new therapeutic tool for future treatment of these tumors.