Nature is an attractive source of new therapeutic agents and a variety of phytochemicals have proved to be very valuable in the prevention and treatment of various diseases. Many of the important drugs isolated from plants during the past 50 years have revolutionized modern medicinal practice (Dar et al., 2017). The use of herbal medicines and phytonutrients or nutraceuticals continues to expand rapidly across the world with many people now resorting to these products for the treatment of various health challenges in different national healthcare settings (WHO, 2004). It is estimated that up to 80% of the world's population living in the developing countries rely on herbal medicinal products as a primary source of healthcare and traditional medical practice as an integral part of the culture in their communities (Ekor, 2013). The medicinal compounds derived from various plants could be divided into three major biochemical classes: alkaloids (vinblastine, vincristine, pilocarpine, berberine, caffeine, piperine etc.), flavonoids (quercetin, kaempferol, chrysin, naringenin, genistein, rutin etc.) and terpenoids (artemisinin, taxol, digitoxin, azadarachtin, camphor, limonene etc.) (Takshak, 2018). These compounds have also gained importance in the area of nutraceuticals, which have positive health effects and may prove to be advantageous in the treatment of diseases like cancer, cardiovascular diseases and diabetes (Crozier et

Rutin or rutoside or sophorin is quercetin-3-rutinoside, a citrus flavonoid glycoside found in a wide variety of plants and has been reported to exhibit anticancer effect against many cancers [1-3]. Molecular docking is a frequently used tool in computer-aided structure-based rational drug design, which may help in evaluating how a small molecule called ligand and the target macromolecule (proteins/enzymes) fit together [4,5]. The anticancer activity of rutin involves inhibition of cell proliferation, a decrease in reduced glutathione (GSH) and induction of apoptosis in cancer cells [2,6]. Cis-diamminedichloroplatinum (II), (CDDP) is a well-known platinum-based cancer chemotherapeutic drug and its anticancer properties have been credited to its DNA binding ability, induction of apoptosis and decrease in glutathione level in cancer cells [7-9]. Therefore, to have a comparative study, CDDP was used as a reference anticancer drug in the present study. Apoptosis is a genetically regulated programmed cell death and the efficacy of anticancer drugs is often measured by their ability to selectively promote apoptosis in cancer cells [10]. B-cell lymphoma-extralarge (Bcl-xL), a member of the Bcl-2 family of proteins, is an antiapoptotic protein, which leads to caspase activation and ultimately, programmed cell death [11]. c-FLIP (cellular FLICE, a FADD-like IL-1β-converting enzyme-inhibitory protein) is a major antiapoptotic protein and an important factor that suppresses cytokine-and chemotherapy-induced apoptosis [12]. GSH, a tri-peptide of L-cysteine, L-glutamic acid and glycine, plays important roles in antioxidant defense, nutrient metabolism, and regulation of cellular processes, including cell differentiation, proliferation and apoptosis [13]. Glutathione S-transferases (GST) catalyzes the conjugation of GSH to xenobiotic substrates for the purpose of detoxification. Glutathione reductase (GR) catalyzes the reduction of glutathione disulphide to GSH [14] .

Cisplatin is an effective anticancer drug used against a variety of cancers. The full therapeutic potential of cisplatin is often hampered due to concurrent development of various side effects in the hosts. Rutin, a naturally occurring bioflavonoid shows several pharmacological activities. It has been earlier reported by us that rutin and cisplatin in combination show better antitumor activity against murine ascites Dalton’s lymphoma. As cisplatin is given to cancer-bearing hosts only, the present study was undertaken to explore the histoprotective effect of rutin against some toxicities induced by cisplatin in tumor-bearing mice. Cisplatin treatment caused severe damages in tissue architecture such as degenerated hepatocytes with nuclear condensation and sinusoidal dilatation in the liver, glomerular deterioration, infiltration of cells, and tubular congestion in the kidney, and vacuolization of Sertoli cells or dense granules in the cytoplasm and damaged seminiferous tubules in the testes. In the rutin plus cisplatin combination-treated mice, all the abnormal tissue architectural features were decreased. Further, as compared to cisplatin treatment, combination treatment did not show any significant elevation in the liver functional biomarkers (serum aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase) and renal functional biomarkers (serum urea and creatinine levels). The combination treatment reduced the sperm abnormalities also as compared to the cisplatin alone treatment. The in vitro hemolysis assay of red blood cells and scanning electron microscopy revealed that combination treatment lessened the cisplatin-induced hemolysis and abnormalities in RBCs. Thus, the present findings demonstrate that rutin has histoprotective ability against cisplatin-induced toxicities in tumor-bearing mice.

Purpose: Cisplatin is a cancer chemotherapeutic drug that has been extensively used in the treatment of a variety of cancers. However, the full usage of cisplatin is limited due to its treatment associated development of multiple side effects in the host. In the present study, the modulatory effect of rutin, a type of flavonoid, on the cisplatin mediated antitumor activity and allied genotoxicity in ascites Dalton’s lymphoma (DL)-bearing mice were investigated. Methods: The antitumor activity was determined by calculating the percent increase in the life span of mice, cell viability and scanning electron microscopy of DL cells. Further, the modulatory effect of rutin on the cisplatin-induced genotoxic effects in the same DL-bearing mice was assessed by the analysis of micronuclei, chromosomal aberration and sperm abnormality. Results: The combination treatment of mice with rutin and cisplatin showed a considerable increase in the life span of the DL-bearing mice depicting better antitumor efficacy. Scanning electron microscopy of these DL cells showed severe membrane deformities in DL cells such as fusion of cell membrane, membrane blebbing, cell shrinkage, membrane folding and loss in microvilli from the tumor cell surface which may lead to cell death. Cisplatin alone treatment caused an increase in the frequency of chromosomal aberrations, micronuclei and sperms abnormality. However, the combination treatment of DL-bearing mice with rutin and cisplatin comparatively reduced these genotoxic effects. Conclusion: The overall findings suggest that rutin enhances the cisplatin-mediated antitumor activity and cytotoxicity against DL cells and at the same time diminishes the genotoxic effects induced by cisplatin in the DL-bearing mice.