Cancer Letters

Cancer Letters

Volume 148, Issue 1, 1 January 2000, Pages 9-17
Cancer Letters

Effect of Withania somnifera on cyclophosphamide-induced urotoxicity

https://doi.org/10.1016/S0304-3835(99)00252-9Get rights and content

Abstract

Administration of an extract from the plant Withania somnifera (Family: Solanaceae) (20 mg/dose/animal; i.p.) for five days along with cyclophosphamide (CTX) (1.5 mmol/kg body wt. i.p.) reduced the CTX induced urotoxicity. Morphological analysis of the bladders of the CTX-treated group showed severe inflammation and dark coloration whereas CTX along with the Withania-treated group showed normal bladder morphology. The extract was found to reduce the protein level in the serum (7.92 g/l) after 4 h of CTX treatment, which was higher in the CTX alone-administered group (11.44 g/l). Blood urea N2 level which was drastically enhanced (136.78 mg/100 ml) 2 after the CTX treatment was significantly reduced (52.08 mg/100 ml) when the animals were treated with Withania extract. Similarly the glutathione (GSH) content in both bladder (1.55 μmol/mg protein) and liver (3.76 μmol/mg protein) was enhanced significantly (P<0.001) in the Withania-treated group compared with the CTX alone-treated animals (bladder 0.5 μmol/mg protein; liver 1.2 μmol/mg protein) Histopathological analysis of the bladder of CTX alone-treated group showed severe necrotic damage where as the Withania somnifera-treated group showed normal bladder architecture.

Introduction

Cyclophosphamide (CTX) is a widely used agent for antineoplastic therapy. CTX, an alkylating agent is inactive in vitro but is activated to cytotoxic metabolites such as 4-hydroxy-cyclophosphamide and phosphoramide mustard [1].

CTX administration causes nausea, vomiting, mucosal ulceration, interstitial pulmonary fibrosis, hepatic toxicity, lymphocytopenia and alopecia. Higher doses of CTX administration produce severe urotoxicity. Mesna, a synthetic compound was found to be effective in reducing the incidence of CTX induced haematuria without interfering with the efficacy of CTX [2].

Withania somnifera, Dunal (common name: Aswagandha) belonging to family Solanaceae is being used in many indigenous drug preparations. Withania extract was found to possess analgesic [3]; antigranuloma [4]; antipyretic and anti-inflammatory [5], [6] activities. Withania treatment was found to increase the total white (WBC) and red blood cell counts and haemoglobin level [7]. The extract was also found to enhance the total WBC and bone marrow cells in animals treated with non-lethal dose of radiation [8].

Withaferin A, a steroidal lactone present in Withania somnifera showed a marked tumour inhibition when tested in vitro against cells derived from human nasopharyngeal carcinoma [9] and experimental mouse tumour [10], [11]. Withanolide D, another steroidal lactone occurring in the leaves of Withania somnifera also showed antitumour activity against Sarcoma-180 and Ehrlisch ascites cells (EAC) [12]. In the present study, we have made a detailed study in the reversal of urotoxicity induced by CTX using Withania extract.

Section snippets

Animals

Swiss Albino mice (20–25 g) were purchased from the National Institute of Nutrition, Hyderabad, India. The animals were fed with normal mouse chow (Lipton, India) and water ad libitum.

Chemicals and reagents

Glutathione (GSH) and 5-5-dithiobis-2-nitrobenzoic acid (DTNB) (Ellman's reagent) were obtained from SISCO Research Laboratory, Bombay. Sodium 2-mercaptoethane sulphoxide (Mesna), total protein and blood urea analysing kits were obtained from SPAN Diagnostic Ltd. All other chemicals used were of analytical reagent

Effect of Withania extract on the morphology of urinary bladder after CTX administration

After 4 h of CTX treatment, control animals showed inflamed bladder with noticeable red coloration where as the CTX along with Withania-treated group showed only a slight inflammation but normal coloration (Table 1). After 24 h the bladders showed severe haemorrhage and coloration in the control group whereas the Withania-treated group showed normal bladder morphology. Even after 48 h the urinary bladder of CTX alone-treated group were severely inflamed and dark coloured whereas those of the

Discussion

One of the major side effects of cyclophosphamide administration is urotoxicity. The deleterious effect of CTX on the bladder include mucosal oedema, haemorrhage, ulceration, subendothehal telangiectasia and, in severe cases, fibrosis of the bladder [14], [15]. The toxicity of CTX is due to the metabolites of the drug. These metabolites react with the urothelium of the bladder.

Since the bladder is the primary storage organ for urine, the content of these metabolites is higher than other areas

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