RESEARCH ARTICLE Anticancer and Radiosensitization Efficacy Of

APJCP.2016.17.9.4367 Anticancer and Radiosensitization Efficacy of NanocompositeWithania somnifera Extract in Mice Bearing Tumor Cells RESEARCH ARTICLE Anticancer and Radiosensitization Efficacy of Nanocomposite Withania somnifera Extract in Mice Bearing Tumor Cells Nadia M Abdallah1, Eman Noaman2, Noaman A Eltahawy2, Abdelfattah M Badawi3, Eman Kandil1*, NA Mansour3, Hebatallah E Mohamed2 Abstract The objective of the present study was to evaluate the anticancer and radio-sensitizing efficacy of aWithania somnifera extract/Gadolinium III oxide nanocomposite (WSGNC) in mice. WSGNC was injected to solid Ehrlich carcinoma-bearing mice via i.p. (227 mg/kg body weight) 3 times/week during 3 weeks. Irradiation was performed by whole body fractionated exposure to 6Gy, applied in 3 doses of 2 Gy/week over 3 weeks. Biochemical analyses as well as DNA fragmentation were performed. Treatment of solid Ehrlich carcinoma bearing mice with WSGNC combined with γ-radiation led to a significant decrease in the tumor size and weight associated with a significant decrease in mitochondrial enzyme activities, GSH content and SOD activity as well as a significant increase in caspase-3 activity, MDA concentration and DNA fragmentation in cancer tissues. Combined treatment of WSGNC and low dose of γ-radiation showed great amelioration in lipid peroxidation and antioxidant status (GSH content and SOD activity) in liver tissues in animals bearing tumors. It is concluded that WSGNC can be considered as a radio-sensitizer and anticancer modulator, suggesting a possible role in reducing the radiation exposure dose during radiotherapy. Keywords: Withania somnifera - gadolinium nanocomposite - tumor - mitochondria Asian Pac J Cancer Prev, 17 (9), 4367-4375 Introduction mechanism of action is similar to the oxygen effect, in which biochemical reactions in the damaged molecules Although radiotherapy is one of the most effective prevent repair of the cellular radiation damage. Free strategies in the treatment of cancers, it is associated radicals such as hydroxyl radicals are captured by the with short and long term side effects on normal electron affinity of the radio-sensitizers, rendering the tissues (Aghamohammadi et al., 2015). Enhancing of molecules incapable of repair (Raviraj et al., 2014). radioresponsiveness of tumors by using radiosensitizers is Nanotechnology is a promising interdisciplinary a promising approach to increase the efficacy of radiation field for developing improved methods of diagnosis therapy (Hematulin et al., 2014). Acquired radiation and treatment of different diseases, including cancer resistance is one of the major causes of radiotherapy (Roblero-Bartolon, and Ramon-Gallegos, 2015). failure and subsequent tumor relapse. Multiple approaches Nanotechnology has been employed to enhance cancer have been utilized to limit the radiation resistance while therapy, via improving the bioavailability and therapeutic simultaneously enhancing the efficacy and safety of efficacy of anti-cancer agents (Basha et al., 2014). radiation therapy. The three major approaches for the The use of nanotechnology in cancer treatment offers improvement of radiation therapy involved (I) enhancing exciting opportunities, including the possibility of radio-sensitization of tumor tissue; (II) reversing the destroying tumors with minimal damage to healthy radiation resistance in tumor tissue; and (III) enhancing tissue by novel targeted drug delivery systems. The pH radio-resistance of the healthy tissue. Nanoparticles have differences between healthy and tumor microenvironment played a key role in the enhancement of the radiation provides pH responsive release of drugs at tumor site via therapy by acting both as a therapeutic as well as a carrier smart nanoparticles (Unsoy et al., 2014). Metal-based for other therapeutics (Kwatra et al., 2013). compounds and nanoparticles (gadolinium in particular) Radio-sensitizers are agents that sensitize the tumor if present in sufficiently high concentrations in the tumors, cells to radiation. These compounds apparently promote metals can act as a radiotherapy adjuvant: they possess fixation of the free radicals produced by radiation an increased capability to absorb the X-ray (ionizing damage at the molecular level (Raviraj et al., 2014). The radiation) with respect to the water-based tissues. Low 1Department of Biochemistry, Faculty of Science, Ain Shams University, 2Department of Radiation biology, National Center for Radiation Research and Technology, (NCRRT), Egyptian Atomic Energy Authority (EAEA), 3Petrochemical Department, Egyptian Petroleum Research Institute *For correspondence: [email protected] Asian Pacific Journal of Cancer Prevention, Vol 17, 2016 4367 Nadia M Abdallah et al energy electrons will be then released close to the metal Nasr City, Cairo, Egypt. The dose rate was 0.5 Gy/minute and, therefore, determine a local dose enhancement during the experimental period. The mice’s whole body (Ceresa et al., 2014). was exposed to gamma rays at a dose of 2 Gy/week up to On the other side, natural compounds are emerging as a total dose of 6Gyduring 3 weeks. effective agents for the treatment of malignant diseases (Lee et al., 2014). The plants used in Ayurvedic medicine, Tumor transplantation which has been practiced in India for thousands of years for A line of Ehrlich ascites carcinoma cells (EAC) used the treatment of a variety of disorders, are rich in chemicals in the present study had been kindly supplied from the potentially useful for prevention and treatment of cancer. National Cancer Institute (NCI), Cairo University, Egypt. Withania somnifera (commonly known as Ashwagandha) It was maintained in female Swiss albino mice by weekly is one of such medicinal plants with anti-carcinogenic intraperitoneal injection of 2.5x106 tumor cells/ mouse (in properties (Senthil et al., 2015), radio-sensitization (Tiwari the right thigh of the lower limb of each mouse). The solid et al., 2014) and antioxidant activities (Ansari et al., 2013). form was obtained by the intramuscular inoculationof Mitochondria are membrane-bound organelles found in 0.2 ml of EAC, contained 2.5 x 106 viable EAC cells. most eukaryoted (Henze et al., 2003). Mitochondria have Mice with a palpable solid tumor diameter (10mm³) that been shown to play an important role in regulating both developed within 10 days after inoculation were used in programmed cell death and cell proliferation (Wallace, the study (Hamburger, 1981). 2008). As the entry point for most electrons into the respiratory chain, NADH dehydrogenase or complex I has Determination of LD50 using experimental animals been suggested as the rate-limiting step in overall electron In screening drugs, determination of LD50 (the dose transfer. It plays a central role in oxidative phosphorylation which has proved to be lethal (causing death to 50% of (Sharma et al., 2009). Intracellular reactive oxygen species the tested group of animals)is usually an initial step in (ROS) may act as signaling molecules for carcinogenesis the assessment and evaluation of the toxic characteristics and cell death induction, a sudden intracellular raise in of a substance. It is an initial assessment of toxic ROS accounting for a pro-death situation (Bras et al., manifestations (provides information on health hazards 2005). They are produced by various enzymatic complexes likely to arise from short- term exposure of drugs) and including NADPH oxidase and mitochondrial electron is one of the initial screening experiments performed transport chain, the latter being considered as the most with all compounds (Akhila et al., 2007). The studied important source of ROS (Fruehauf and Meyskens, 2007). compound was administered in graduated doses and LD50 In view of these considerations the aim of the current study was determined (Narang and Desai, 2009). The optimum was to evaluate the efficacy of WSGNC as an anticancer selected dose for evaluating the in vivo antitumor activity and radio-sensitizer agent. of the tested compound was calculated approximately as (1/5) of its LD50 value. Materials and Methods Treatment Chemicals Withania somnifera extract/gadolinium III oxide Gadolinium III oxide was purchased from sigma- nanocomposite (WSGNC) was injected via intraperitoneal Aldrich Company. The shade dried roots of Withania injection of animals at a dose of 227 mg/kg body weight somnifera Dunal had been supplied from the Agricultural for3times/week during 3 weeks. Seeds, Spices and Medical Plants Company, Egypt. Preparation of Withania somnifera extract/gadolinium III Experimental animals: oxide nanocomposite (WSGNC) Sixty female Swiss albino mice, weighing 25g were The shade dried roots were powdered coarsely and used in the course of the present work. The animals were the powder was extracted (soxhlet) with petroleum housed in especially designed plastic cages (15 mouse/ ether and 70% ethyl alcohol in 1:10 w/v ratio for 72 h cage), under normal temperature, pressure, humidity, good according to (Wanger et al., 1984). 15 g of extracted ventilation and illumination conditions. Animals were fed Withania somnifera was placed in a beaker, 10 ml dimethyl on pellets diet supplied with excess of water. All animal sulphoxide (DMSO) were added (as solvent) and the procedures were performed in accordance with the Ethics reaction mixture put on the hot plate, after 10 minutes 5 Committee of the National Research Centre conformed to g of Gadolinum III oxide nano powder were added. The the “Guide for the care and use

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