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1 Apr GBCC in JeJu Island Sensitization of breast cancer cells to chemotherapeutic drugs by metabolic regulation InChul Park, Ph. D. Korea Institute of Radiological & Medical Sciences (KIRAMS)

2 The Hallmarks of cancer2000 yr

3 The Hallmarks of cancer2011 yr abnormal metabolic pathways evading the immune system

4 What is the Warburg Effect?

5 The number of publications using the term Warburg effect Number of publications per year found in the Web of Science with the search words Warburg effect AND (cancer OR tumor) Cancer & Metabolism 2016

6 Some of the most striking changes of tumor cellular bioenergetics Elevation of glucose uptake and glycolysis rate Increase in glutaminolytic flux Upregulation of amino acid and lipid metabolism Induction of pentose phosphate pathway, and macromolecule biosynthesis

7 The Warburg Effect: How Does it Benefit Cancer Cells? Rapid ATP synthesis the production of lactate from glucose occurs times faster than the complete oxidation of glucose in the mitochondria Biosynthesis adaptation mechanism to support the biosynthetic requirements of uncontrolled proliferation Tumor microenvironment present an advantage for cell growth in a microenvironment Cell signaling confers direct signaling functions to tumor cells by regulation of ROS and histone acetylation

8 The impacts of tumor suppressors and oncogenes on cancer metabolic reprogramming (1)

9 The impacts of tumor suppressors and oncogenes on cancer metabolic reprogramming (2)

10 Metabolic pathways prominent in malignant cells

11 The Warburg Effect: potential targets for tumor therapy The reversing the Warburg effect compromises the tumorigenecity of tumor cells, suggesting that targeting the metabolic changes could be an effective strategy for cancer treatment.

12 The potential targets and the corresponding chemicals

13 Association of PDKs overexpression with patient mortality Int. J. Biol. Sci, 2015

14 The function of pyruvate dehydrogenase kinase (PDK) in the regulation of pyruvate dehydrogenase(pdc)

15 Mechanism of DCA in cancer: DCA inhibits pyruvate dehydrogenase kinase (PDK) resulting in activation of pyruvate dehydrogensae

16 Chemical structures and mechanism of action of mitaplatin After crossing the plasma membrane, mitaplatin becomes reduced to release of the active drugs cisplatin and DCA. PNAS, (52):

17 DCA as a possible anticancer drug DCA increases the antitumor effects of capecitabine in a mouse B16 melanoma allograft and a human NSCLC A549 xenograft Cancer Chem. Pharm., 2013 PDK1 inhibition is a novel therapeutic target in multiple myeloma Br. J. Cancer 2013 DCA inhibits aerobic glycolysis in MM cells and increases sensitivity to bortezomib. Br. J. Cancer 2013 Activating oxidative phosphorylation by a PDK inhibitor overcomes sorafenib resistance of HCC Br. J. Cancer 2013 Combination of sulindac and DCA kills cancer cells via oxidative damage PLoS One 2012 Activation of mitochondrial oxidatin by PDK2 inhibition reverses cisplatin resistance in head and neck Cancer Lett. 2016

18 Results

19 Cellular function of S6K1

20 ps6k1 expression might be a marker for endocrine therapy resistance in patients with HR () tumors 304 breast cancer tissues Breast Cancer Res Treat. 2011

21 S6K1 inhibition enhances tamoxifeninduced cell death in ER() breast cancer cells Cell Biol. Toxicol. 2013

22 Conclusion (1) Activation of S6K1 by phosphorylation is associated with resistance to tamoxifen in estrogen receptorpositive breast cancer.

23 S6K1 activity does not change in MCF7 cells under glucose starvation Biochem Biophys Res Commun. 2013

24 Inhibition of S6K1 enhances glucose deprivationinduced cell death Biochem Biophys Res Commun. 2013

25 Combination effect of DCA and S6K1 inhibition on cell death of breast cancer cells J. Can. Res. & Clin. Oncol. 2015

26 Conclusion (2) Activation of S6K1 is responsible for survival against nutrient stresses including glucose limitation. Inhibition of S6K1 enhanced dichloroacetateinduced cell death in breast cancer cells.

27 We next investigated whether targeting cancer metabolism with dichloroacetate overcome tamoxifen resistance in breast cancer cells.

28 Inhibition of PDK enhanced tamoxifeninduced cell death of MCF7 cells CTL Tamoxifen DCA Tam DCA 35 24hr 48hr Cell death (%) hr 0 Tamoxifen DCA 24hr 48hr Manuscript in preparation

29 DCA reduces the EGFR expression in MCF7 cells EGFR DCA (mm) EGFR PPDH PDH βactin FGFR1 FGFR4 HER2/Neu ERα PDK1 βactin Manuscript in preparation

30 Downregulation of EGFR by the combined treatment of tamoxifen and DCA CTL Tamoxifen/DCA CHX (h) Tamoxifen DCA MG132 EGFR EGFR βactin βactin Manuscript in preparation

31 Downregulation of EGFR by p38 kinase activation Tam/DCA Ctl (h) EGFR PEGFR (S1046/1047) Pp38 Tam/DCA Ctl SB (μm) EGFR βactin p38 βactin Manuscript in preparation

32 Overexpression of receptor tyrosine kinase in TAM resistance cells Tamoxifen conc. (um) parental Tam resistant EGFR FGFR1 HER2/Neu ERα βactin Manuscript in preparation

33 DCA induced cell death in tamoxifen resistant cells 120 CTL Tamoxifen DCA Tam DCA Cell viability (% of CTL) Tamoxifen DCA Tamoxifen DCA EGFR βactin Manuscript in preparation

34 Conclusion (3) Dichloroacetate could overcome tamoxifen resistance by downregulation of EGFR in protein levels.

Metformin is in the biguanide class is the firstline medication for the treatment of type 2 diabetes which is taken by mouth is generally well tolerated.

35 Metformin is in the biguanide class is the firstline medication for the treatment of type 2 diabetes which is taken by mouth is generally well tolerated. is available as a generic medication show a favorable effect on cancer inhibit the mtor by AMPK activation inhibit the electron transport system in mitochondria Clin Cancer Res Published OnlineFirst March 28, 2014

36 Combined effect of metformin and DCA on cell death Biochem Biophys Res Commun. 2016

37 Hypoxia suppressed the metabolic stressinduced cell death Biochem Biophys Res Commun. 2016

38 Resistance to DCA/metformininduced cell death by HIF1alpha Biochem Biophys Res Commun. 2016

39 Conclusion (4) Based on these findings, we propose that targeting HIF1a is necessary for cancer metabolism targeted therapy.

40 Expression of TRAIL receptor DR5 is induced under hypoxia condition TNFrelated apoptosisinducing ligand (TRAIL) (DR4/DR5) DR4 DR5 βactin Metformin & DCA Hypoxia (1% O 2 ) Manuscript in preparation

41 TRAIL could overcome the effects of hypoxia on metabolic stressinduced cell death 80 *** Cell death (%) Cleaved PARP βactin Metformin & DCA Hypoxia (1% O 2 ) CTL TRAIL Manuscript in preparation

42 Conclusion (5) TRAIL overcomes the HIF1alpha suppression of cell death induced by dichloroacetate and metformin

43 Conclusion Impairment of tumor metabolism could be able to improve therapeutic efficacy in breast cancer

44 Acknowledgement Seo SK, Ph. D, KIRAMS Hong SE, MS, KIRAMS Jin HO, Ph. D, KIRAMS Woo SH, Ph. D, KIRAMS Ye SK, Prof, Seoul Nat l. Univ. College of Medicine Lee YH, Prof, Yonsei College of Medicine An S, Prof, KonKuk University Noh WC, M.D., Ph. D., Korea Cancer Center Hospital

45 Thank you for your attention!

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract