Combination of Fe/Cu –chelators and docosahexaenoic acid: an exploration for the treatment of colorectal cancer

// Nanhui Yu 1, 2 , Hong Zhu 1 , Yuan Yang 3 , Yiming Tao 1 , Fengbo Tan 1 , Qian Pei 1 , Yuan Zhou 1 , Xiangping Song 1 , Qiurong Tan 2 and Haiping Pei 1 1 Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha 410008, P.R. China 2 Department of Pharmacy, Changsha Hospital for Maternal and Child Health Care, Changsha 410007, P.R. China 3 Dong Medicine Key Laboratory of Hunan Province, Department of Laboratory medicine, Hunan University of Medicine, Hunan 418000, P.R. China Correspondence to: Haiping Pei, email: haiping1977pei@163.com Keywords: combination of Fe/Cu –chelators and docosahexaenoic acid, myeloid cell leukemia-1 (Mcl-1), apoptosis, ubiquitination, colorectal cancer Received: November 25, 2016     Accepted: April 24, 2017     Published: May 11, 2017 ABSTRACT Colorectal cancer (CRC) is one of the major causes of cancer deaths in the world. 5-fluorouracil (5-FU) -based chemotherapy is a common choice for patients with CRC; unfortunately, the benefit is rather limited due to the acquisition of drug resistance. Therefore, the alternative therapeutic strategies are required. The activation of autophagic mechanism was considered as the main cause of the acquisition of drug resistance in 5-FU treatment. Docosahexaenoic acid (DHA), a fatty acid, has been regarded as an efficient anticancer agent and can improve the drug resistance in conventional cancer therapy by a low basal level of autophagy in colon cancer cells. Moreover, removal of iron or copper by metal chelators could cause ROS levels increase and mediate cancer cell cytotoxicity led by autophagy. In the present study, we constructed a combination of 5-FU, 1:1 mixture of metal chelators di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone hydrochloride (DpC) and N, N, N’, N’-tetrakis-[2-pyridylmethyl]-ethylenediamine (TPEN) named DTN, and DHA to evaluate the anticancer effect of this combination, compared to the traditional 5-FU-based chemotherapy; further we investigated the underlying mechanism. Through inducing ROS-mediated degradation of Mcl-1 ubiquitination, the triple combination of 5-FU, DTN and DHA resulted in the elevated apoptosis in CRC cells, thus to reduce the tumor size and weight. Taken together, this study suggests the triple combination of 5-FU+DTN+DHA exhibits an effective anticancer activity of overcoming drug resistance in colorectal cancer, mechanism as the elevated apoptosis mediated by an increase of ROS and Mcl-1 ubiquitination, may be a novel strategy for clinical colon cancer treatment.