Aqueous <i>Oldenlandia diffusa</i> extracts inhibits colorectal cancer cells via activating AMP-activated protein kinase signalings

Abstract

// Pei-Hua Lu 1, 2, * , Min-Bin Chen 3, * , Chao Ji 4, * , Wen-Ting Li 1 , Mu-Xin Wei 5 , Mian-Hua Wu 1 1 Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, 210023, China 2 Department of Medical Oncology, Wuxi People&rsquo;s Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, Jiangsu, China 3 Department of Medical Oncology, Kunshan First People&rsquo;s Hospital Affiliated to Jiangsu University, Kunshan, 215300, Jiangsu, China 4 Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China 5 Department of Traditional Chinese Medicine, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China * These authors have contributed equally to this work Correspondence to: Mian-Hua Wu, email: duoduoli772@sina.com Keywords: colorectal cancer (CRC), Oldenlandia diffusa (OD) extracts (ODE), AMP-activated protein kinase (AMPK), p53 and mammalian target of rapamycin (mTOR) Received: April 18, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: June 03, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: June 13, 2016 ABSTRACT Here we evaluated the anti-cancer activity of aqueous Oldenlandia diffusa (OD) extracts (ODE) in colorectal cancer (CRC) cells. We showed that ODE exerted potent anti-proliferative, cytotoxic and pro-apoptotic activities against a panel of established CRC lines (HCT-116, DLD-1, HT-29 and Lovo) and primary (patient-derived) human CRC cells. ODE activated AMP-activated protein kinase (AMPK) signaling, which led to subsequent mTORC1 inhibition and Bcl-2/HIF-1&alpha; downregulation in CRC cells. In ODE-treated CRC cells, AMPK&alpha;1 formed a complex with p53. This might be important for p53 activation and subsequent cancer cell apoptosis. Inhibition of AMPK signaling, though dominant negative (dn) mutation or shRNA/siRNA knockdown of AMPK&alpha;1 attenuated ODE-exerted CRC cytotoxicity. In vivo , i.p. administration of ODE inhibited HCT-116 xenograft tumor growth in SCID mice. In addition, AMPK activation, mTORC1 inhibition and p53 activation were observed in ODE-treated HCT-116 xenograft tumors. These results suggest that ODE inhibits CRC cells in vitro and in vivo , possibly via activation of AMPK-dependent signalings.