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Metformin AND DCA

Sung-Eun Hong, Chang Soon Kim, Sungkwan An, Hyun-Ah Kim, Sang-Gu Hwang, Jie-Young Song, Jin Kyung Lee, Jungil Hong, Jong-Il Kim, Woo Chul Noh, Hyeon-Ok Jin, In-Chul Park
Previous studies have shown that hypoxia can reverse DCA/metformin-induced cell death in breast cancer cells. Therefore, targeting hypoxia is necessary for therapies targeting cancer metabolism. In the present study, we found that TRAIL can overcome the effect of hypoxia on the cell death induced by treatment of DCA and metformin in breast cancer cells. Unexpectedly, DR5 is upregulated in the cells treated with DCA/metformin, and sustained under hypoxia. Blocking DR5 by siRNA inhibited DCA/metformin/TRAIL-induced cell death, indicating that DR5 upregulation plays an important role in sensitizing cancer cells to TRAIL-induced cell death...
September 23, 2016: Biochemical and Biophysical Research Communications
Bo Li, Xinzhe Li, Zhenhong Ni, Yan Zhang, Yijun Zeng, Xiaohuan Yan, Yan Huang, Jintao He, Xilin Lyu, Yaran Wu, Yuting Wang, Yingru Zheng, Fengtian He
Both dichloroacetate (DCA) and metformin (Met) have shown promising antitumor efficacy by regulating cancer cell metabolism. However, the DCA-mediated protective autophagy and Met-induced lactate accumulation limit their tumor-killing potential respectively. So overcoming the corresponding shortages will improve their therapeutic effects. In the present study, we found that DCA and Met synergistically inhibited the growth and enhanced the apoptosis of ovarian cancer cells. Interestingly, we for the first time revealed that Met sensitized DCA via dramatically attenuating DCA-induced Mcl-1 protein and protective autophagy, while DCA sensitized Met through markedly alleviating Met-induced excessive lactate accumulation and glucose consumption...
July 19, 2016: Oncotarget
Rebecca Voltan, Erika Rimondi, Elisabetta Melloni, Paola Gilli, Valerio Bertolasi, Fabio Casciano, Gian Matteo Rigolin, Giorgio Zauli, Paola Secchiero
Metformin and the mitochondrial targeting dichloroacetate (DCA) have recently received attention due to their ability to inhibit anaerobic glycolysis, which renders most cancer cells resistant to apoptosis induction. We observed that Metformin alone exhibited a dose-dependent anti-leukemic activity in both B leukemic cell lines and primary B-chronic lymphocytic leukemia (B-CLL) patients' cells and its anti-leukemic activity was enhanced when used in combination with DCA. In order to overcome the problems of poor bioavailability and cellular uptake, which limit DCA efficacy, we have designed and synthetized cocrystals consisting of Metformin and DCA (Met-DCA) at different stoichiometric ratios...
April 5, 2016: Oncotarget
Sung-Eun Hong, Hyeon-Ok Jin, Hyun-Ah Kim, Min-Ki Seong, Eun-Kyu Kim, Sang-Kyu Ye, Tae-Boo Choe, Jin Kyung Lee, Jong-Il Kim, In-Chul Park, Woo Chul Noh
Recently, targeting deregulated energy metabolism is an emerging strategy for cancer therapy. In the present study, combination of DCA and metformin markedly induced cell death, compared with each drug alone. Furthermore, the expression levels of glycolytic enzymes including HK2, LDHA and ENO1 were downregulated by two drugs. Interestingly, HIF-1α activation markedly suppressed DCA/metformin-induced cell death and recovered the expressions of glycolytic enzymes that were decreased by two drugs. Based on these findings, we propose that targeting HIF-1α is necessary for cancer metabolism targeted therapy...
January 8, 2016: Biochemical and Biophysical Research Communications
Viharkumar Patel, Xueli Zhang, Nicolas A Tautiva, Akwe N Nyabera, Opeyemi O Owa, Melvin Baidya, Hee Chang Sung, Pardeep S Taunk, Shahrzad Abdollahi, Stacey Charles, Rachel A Gonnella, Nikhita Gadi, Karen T Duong, Janelle N Fawver, Chongzhao Ran, Tuula O Jalonen, Ian V J Murray
Small molecule interactions with amyloid proteins have had a huge impact in Alzheimer's disease (AD), especially in three specific areas: amyloid folding, metabolism and brain imaging. Amyloid plaque amelioration or prevention have, until recently, driven drug development, and only a few drugs have been advanced for use in AD. Amyloid proteins undergo misfolding and oligomerization via intermediates, eventually forming protease resistant amyloid fibrils. These fibrils accumulate to form the hallmark amyloid plaques and tangles of AD...
2015: Current Alzheimer Research
Allison B Haugrud, Yongxian Zhuang, Joseph D Coppock, W Keith Miskimins
The unique metabolism of breast cancer cells provides interest in exploiting this phenomenon therapeutically. Metformin, a promising breast cancer therapeutic, targets complex I of the electron transport chain leading to an accumulation of reactive oxygen species (ROS) that eventually lead to cell death. Inhibition of complex I leads to lactate production, a metabolic byproduct already highly produced by reprogrammed cancer cells and associated with a poor prognosis. While metformin remains a promising cancer therapeutic, we sought a complementary agent to increase apoptotic promoting effects of metformin while attenuating lactate production possibly leading to greatly improved efficacy...
October 2014: Breast Cancer Research and Treatment
Yong Won Choi, In Kyoung Lim
To investigate sensitization of metformin-cytotoxicity, cancer cells were treated with dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK). Metformin-cytotoxicity was mainly dependent on glucose availability and reducing power generated by pentose phosphate pathway, whereas DCA cotreatment enhanced metformin-cytotoxicity via reprogramming glucose metabolism by inhibiting PDK and increasing mitochondrial respiration. DCA cotreatment elicited cell death rather than cell survival despite high glucose and high GSH condition...
May 1, 2014: Cancer Letters
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