Improvement of chemotherapy through reducing of cachexia by using Citrus unshiu peel extract

Abstract

.Colorectal cancer (CRC) is now one the fourth cause of mortality and morbidity due to cancer throughout the globe. Cachexia is more prevalent in patients with this cancer and has a negative effect on response to chemotherapy and radiotherapy. Inflammatory cytokines such as TNF-α, IL-1β, and IL-6 could play a key role in cachexia. Moreover strong chemotherapy medications such as doxorubicin have complications such as toxicity and cachexia. Citrus unshiu Peel have been used as traditional herbal drugs for the treatment of cancer in traditional oriental medicine (TOM). Since its main components have anti-inflammatory effects, we evaluated the anti-cachexia activity in order to support the traditional usage of Citrus unshiu peel. Aim of the study; We aimed to assess the preventive or therapeutic effect of Citrus unshiu Peel Extract (CUPE) on cachexia by reducing of inflammatory cytokines in mice bearing C26 tumor. Also the contribution role of CUPE has evaluated on improvement of chemotherapy through reducing of inflammatory cytokines. Materials and Methods; The CUPE was prepared by Soxhlet extractor and quantitative and qualitative analysis of aqua extract was performed by high performance liquid chromatography (HPLC). C26 tumor bearing BALB/c male mice were immunized with different formulation of oral Prophylactic-therapeutic CUPE and/or intraperitoneal doxorubicin and then were monitored for weight gain, food intake and tumor size throughout the study. On the 32nd day after tumor injection, inflammatory cytokines levels, IL6, TNF-α and IL-1β were evaluated by Enzyme-linked Immunosorbent Assay (ELISA) and Malondialdehyde- Thiobarbituric acid (MDA) levels were measured by standard method. Results; Oral administration of CUPE in both prophylactic and therapeutic formulation to C26 adenocarcinoma bearing mice reduced the weight loss, tumor volume, and serum MDA levels compared with untreated tumor-bearing mice and Doxorubicin (Dox) groups. Also, the combination therapy of (CUPE + Dox) leads to reducing the levels of serum IL-6, TNF-α, IL-1β and tumor volume compared with untreated tumor-bearing mice and Dox groups. Serum MDA levels were considerably reduced by combination therapy of (CUPE + Dox) compared with Dox groups. Conclusions; These findings confirm the safety and efficacy of CUPE on C26 adenocarcinoma bearing mice as pure and adjuvant therapy, the results of which might be used in further human studies as a valuable natural anticancer agent alone or in combination with chemotherapy. Also the results showed that simultaneous application of CUPE and Dox leads to significant reduction of cachexia from the Dox chemotherapy.

Keywords: Chemotherapy; Citrus unshiu; Inflammatory cytokines; colon cancer.