Modulatory role of resveratrol on cytotoxic activity of cisplatin, sensitization and modification of cisplatin resistance in colorectal cancer cells

Abstract

Colorectal cancer (CRC) is a leading cause of cancer-associated mortality worldwide. Cisplatin (CIS) is one of the most active cytotoxic agents in current use and it has proven efficacy against various human malignancies. However, its clinical usefulness has been restricted by detrimental side effects, including nephrotoxicity and myelosuppression. The aim of the present study was to attempt to decrease the required dose of CIS, in order to minimize its side effects, and increase its capability to arrest, delay or reverse carcinogenesis. In addition, the present study aimed to ameliorate CIS-resistance in CRC cells, using the natural compound resveratrol (RSVL). RSVL (3,4', 5-trihydroxy-trans-stilbene) is a naturally occurring polyphenol present in the roots of white hellebore (Veratrum grandiflorum O. Loes) and extracted from >70 other plant species. RSVL can exert antioxidant and anti-inflammatory activities, and it has been shown to be active in the regulation of numerous cellular events associated with carcinogenesis. The present study evaluated the effects of RSVL on sensitization of both parent and CIS-resistant HCT-116 CRC cells to the action of cisplatin. The CIS was administered at a dose of 5 and 20 µg/ml, and CIS cytotoxicity, apoptosis, cell cycle and cisplatin cellular uptake were examined in the presence and absence of RSVL (15 µg/ml). RSVL treatment showed anti-proliferative effects and enhanced the cytotoxic effects of cis against the growth of both parent and CIS-resistant HCT-116 CRC cells, with a half maximal inhibitory concentration of 4.20 µg/ml and 4.72 µg/ml respectively. RSVL also induced a significant increase in the early apoptosis fraction and enhanced the subsequent apoptotic effects of CIS. The cellular uptake of CIS was significantly increased in the presence of RSVL, as compared with CIS treatment alone, and RSVL treatment sensitized the CIS-resistant HCT-116 cells. In conclusion, RSVL treatment increased the cytotoxic activity of CIS against the growth of both parent and CIS-resistant HCT-116 CRC cells.

Natural compounds as potential adjuvants to cancer therapy: Preclinical evidence

“…Additionally, ellagic acid and resveratrol prevented induction of resistance in ovarian cancer towards cisplatin (Engelke, Hamacher, Proksch, & Kassack, ). (Z)‐3,4,3′,5′‐tetramethoxystilbene, a stilbenoid, increased antitumor efficacy of cisplatin in cisplatin‐resistant osteosarcoma cells in in vitro and in vivo (H. Xu, ), and another stilbenoid, resveratrol, increased cisplatin uptake and efficacy (Osman et al, ). β‐Phenylethyl isothiocyanate and 6‐gingerol down‐regulated intracellular GSH level and concurrently reversed resistance to doxorubicin and cisplatin in resistant‐uterine sarcoma cells (Angelini, Conti, Ciofani, Cuccurullo, & Di Ilio, ; W. J. Wu et al, ).…”

Phytotherapy of nephrotoxicity-induced by cancer drugs: an updated review

“…Resveratrol is a protective agent against chemotherapy drug-induced nephrotoxicity. This compound has antioxidant, anti-inflammatory, and antiapoptotic activities and can suppress cisplatin-induced cytotoxic effects ( 54 - 56 ). Indications of renal injury and toxicity such as increased serum creatinine level and urine proteins in resveratrol-treated mice were reported to be lower than those in controls.…”

The Effect of Resveratrol or Curcumin on Head and Neck Cancer Cells Sensitivity to the Cytotoxic Effects of Cisplatin

“…Natural compounds must be well tolerated and have long-lasting benefits. They can also act at the level of different signaling pathways responsible for the tumorigenesis process in HNSCC, which recommends them as agents with multiple molecular targets [ 73 , 74 ]. The experimental approch of this study focused on the enhancing chemotherapy response while lowering side effects and the incidence of drug resistance.…”