Synergistic Effect of Resveratrol with 5-Fluorouracil in Chemotherapy of Induced Oral Squamous Cell Carcinoma

Abstract

Introduction: Oral cancer is a common cause of death in human, its treatment involves chemotherapy. However, toxicity is an obstacle to this treatment. Studies suggested that combining chemotherapy with specific antioxidants can improve drug efficacy and reduce the chemotherapeutic drug toxicity. Aim: To evaluate the anticancer effect of resveratrol alone or combined with 5-Fu on experimentally induced tongue cancer. Materials and Methods: Forty male albino rats were divided into five groups: Group I: untreated (negative control), group II: positive-control, receiving 50 ppm 4-NQO in drinking water, group III: received i.p injection of (5-FU), group IV: oral-administration of resveratrol (RV), and group V: receiving both RV and 5-FU. Before euthanasia, blood samples were withdrawn to evaluate serum level of ALT, AST and creatinine. After euthanasia, the tongues were surgically excised, and processed for H&E, and mutant p53 IHC. The mean of positive cells/group were statistically analyzed. Results: Group I showed normal tongue mucosa with negative immune expression of mutant p53 cells. Group II revealed malignant ulcers in a form of well/moderately differentiated SCC, and the highest mean of mutant p53 immuno-expression. Group III showed mild dysplasia of the tongue epithelium with a significant regression of the mean number of mutant p53 positive-cells. Group IV expressed moderate dysplasia, with a significantly high mean of mutant p53. Group V showed mild dysplasia with comparable mean of mutated p53 positive cells. Regarding toxicity, group II showed the maximum elevation of ALT, AST, and serum creatinine. These levels were decreased significantly in the treated groups. Conclusion: Resveratrol has a promising therapeutic effect against 4NQO-induced tongue cancer as 5-FU alone. It diminished the cytotoxic effect of 5-FU and enhanced normal histologic-appearance of tongue mucosa when used in combination.

Bioactive Compounds from Plants Used as Therapeutic Agents in Biomedical Applications – a Literature Review –

“…Also RES can increase the number of S phase cells that is a reason why the produced synergy effect increased the percentage of apoptotic cells, activated the level of caspase-3, cleaved PARP and p53 protein and finally increased the Bax/Bcl-2 ratio [85]. The synergy effect on the oral squamous cell carcinoma and the combined therapy had regressed this affection to mild dysplasia [86]. In colon cancer the combination showed attenuation of injury severity.…”

In Vitro Assessment of the Cytotoxic Effect of 5-Fluorouracil, Thymoquinone and their Combination on Tongue Squamous Cell Carcinoma Cell Line

“…The 5-Fluoro-2,4(1H,3H)-pyrimidinedione (5-FU) family, commercially known as Fluorouracil are antimetabolite drugs that work by inhibiting essential biosynthetic processes, or by being incorporated into macromolecules, such as DNA and RNA, resulting in inhibition of their normal function [7,8]. It is a pyrimidine analogue that was first discovered in 1957 and remains a crucial chemotherapeutic drug for various solid tumors including OSCC [7,9].…”

“…It is converted intracellularly to several active metabolites: fluorodeoxyuridine monophosphate (FdUMP), fluorodeoxyuridine triphosphate (FdUTP), and fluorouridine triphosphate (FUTP). These active metabolites disrupt RNA synthesis and the action of thymidylate synthase (TS) [7,9,8]. Moreover, the toxic side effects that accompany therapeutic dosages of 5-FU have limited its systemic use in tumor therapy [6].…”

Enhanced Effect of Resveratrol on Hepatocellular Carcinoma of Rats Treated with 5-Fluorouracil

“…10 rats were intraperitoneally injected with a single dose of freshly prepared DEN (200 mg/kg b.w), 2 weeks later, they were subcutaneously injected with CCl 4 once weekly (3 mL/ kg b.w) for 6 weeks to enhance DEN carcinogenicity as a model for liver cancer (Aboubakr et al, 2017;El-Tabl et al, 2019). 30 rats received DEN as in the previous group, and then treated either with 5-FU or RES or both of them as following; 10 HCC animals were intraperitoneally injected by 5-Fluorouracil (12.5mg/kg, 3 days weekly (day after day) for 2 months) (Soliman et al, 2018), 10 HCC-rats were orally administrated resveratrol dissolved in DMSO (200 μg/kg b.w daily for 2 months) (Soliman et al, 2018;El-Oraby et al, 2020), and 10 HCC rats treated with both 5-FU and RES (6.25 mg 5-FU/kg (ip) on days 1, 3, and 5 of the week for 2 months, and in the same period, rats were daily oral given 100μg RES/kg).…”

“…Adikwu et al (2019) reported that RES had a therapeutic benefit in nephrotoxicity in rats caused by 5-FU, which further elucidates the protective impact of RES on normal cells. El-Oraby et al (2020) reported the synergistic impacts of resveratrol with 5-fluorouracil against oral squamous cell carcinoma in rats.…”