herg1 channels: from an2targets to novel therapeu2c targets in oncology
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1 herg1 channels: from an2targets to novel therapeu2c targets in oncology Annarosa Arcangeli 1, Andrea Becche- 2, Olivia Crociani, Massimo D Amico 1, Luca Gasparoli 1, Marika Masselli, Serena Pillozzi 1, Kenneth Mugridge 3 and Wolfgang Tiedke 3. 1 Department of Experimental Pathology and Oncology, University of Florence and IsPtuto Toscano Tumori (ITT), Florence, Italy; 2 Department of Biotechnology and Biosciences, University of Milano Bicocca, Milano, Italy; 3 BlackSwan Pharma GmbH, Leipzig, Germany.
2 Disclosures No conflict of interest to declare
3 herg1 POTASSIUM CHANNELS
4 Several drugs block herg1 channels drug induced LQT2 ANTITARGET Specific herg1 blockers E4031 WAY 123,398
5 herg1 is overexpressed in several types of Acute myeloid and lymphoblaspc leukemias Hofmann et al., J.Biol.Chem., 2001; Pillozzi et al., Leukemia, 2002; Pillozzi et al., Blood, 2007; Pillozzi et al., Blood, 2011 Endometrial Cancers Cherubini et al., Br. J. Cancer, 2000 Neuroblastomas Arcangeli et al., J. Cell Biol., 1993; Arcangeli et al., J.Physiol., 1995; Arcangeli et al., Eur.J.Neurosci, 1997; Crociani et al., Mech.Devel., 2000; Crociani et al., J. Biol. Chem., 2003 Colorectal and Gastric Cancers Lastraioli et al., Cancer Res. 2004; Lastraioli et al., J.Cell.Physiol., Glioblastoma Masi et al., Br. J. Cancer, human cancers
6 herg1 regulates different biological func2ons in cancer cells Cell prolifera2on (myeloid leukemias) Drug induced apoptosis (lymphoblas2c leukemias) Tumor cell invasion and metasta2c spread (colorectal cancers) Trans endothelial migra2on and invasion of extramedullary organs (myeloid leukemias) VEGF A secre2on and angiogenesis (astrocytomas; gastric and colorectal cancers)
7 herg1: new target in oncology? Adverse cardiac effects!
8 Differences between cardiac and tumour herg1 Biophysical Molecular FuncPons
9 Biophysical characterispcs of herg1 channels I (K)ERG quickly inac2vates afer opening at posi2ve poten2als Inac2va2on is faster than ac2va2on Recovery from inac2va2on is faster than deac2va2on
10 In the heart: herg1 = Ikr herg1 channels ac2vate slowly and inac2vate rapidly during the ini2al phases of the cap; as repolariza2on begins, herg1 channels rapidly recover from inac2va2on and generate an appreciable outward current. In cancer cells: herg1 channels exibit a significant steady state conductance at membrane poten2als around 40 mv Membrane poten2al
11 Molecular characteris2cs of herg1 in cancer cells A
12 Func2ons of herg1 in cancer cells
13 herg1 channels co assemble with integrins and modulate integrin dependent signalling.
14 PotenPal approaches to improve the efficacy and safety of herg1 channel targepng in oncology: Use of non torsadogenic herg1 blockers (e.g.erythromycin, ser2ndole). Use of compounds which bind herg1 channels in the open state (D Roscovi2ne). Use/development of compounds which selec2vely inhibit tumour specific herg1 isoform(s) Development of compounds (an2bodies, pep2des) which disassemble the ion channel/ integrin complex.
15 PotenPal approaches to improve the efficacy and safety of herg1 channel targepng in oncology: Use of non torsadogenic herg1 blockers (e.g.erythromycin, ser2ndole). Use of compounds which bind herg1 channels in the open state (D Roscovi2ne). Use/development of compounds which selec2vely inhibit tumour specific herg1 isoform(s) Development of compounds (an2bodies, pep2des) which disassemble the ion channel/ integrin complex.
16 Erythromycin Ser2ndole
17 State dependent block of HERG potassium channels by R roscovi)ne: implicapons for cancer therapy Ganapathi SB et al., Am J Physiol Cell Physiol 296: C701 C710, R RoscoviPne
18 Serena Pillozzi β1/herg1/cxcr4 complex SURVIVAL (ILK, AKT)
19 The complex is relevant to drive survival signals which is the effect of blocking herg1 channels on drug induced apoptosis?
20 The addipon of herg1 blockers shortcomes the protecpve effect of Bone Marrow Stromal Cells on Doxorubicin (Prednisone, Methotrexate, L asparaginase) induced apoptosis apopto2c cells (%) (Annexin+/PI )
21
22
23 Primary B ALL
24 E4031 synergizes with chemotherapeu2c drugs on MSC
25 Effects of the herg1 blocker E4031 in vivo
26 E4031 has a therapeu2c effect in vivo on B ALL (697 cells): increase in survival
27 E4031 has a therapeu2c effect in vivo on B ALL (cor2costeroid resistant REH cells)
28 Non torsadogenic herg1 blockers (Erythromycin and Ser2ndole) and R Roscovi2ne have the same effects of E4031
29 Effects of Erythromycin on primary B ALL
30 PotenPal approaches to improve the efficacy and safety of herg1 channel targepng in oncology: Use of non torsadogenic herg1 blockers (e.g.erythromycin, ser2ndole). Use of compounds which bind herg1 channels in the open state (D Roscovi2ne). Use/development of compounds which selec2vely inhibit tumour specific herg1 isoform(s) Development of compounds (an2bodies, pep2des) which disassemble the ion channel/ integrin complex.
31 Leipzig, Germany W. Tiedke
32 Effects of CD on prolifera2on of leukemia cell lines and herg1a/herg1b expressing cells :LD50 values (comparison with E 4031)
33 Massimo D Amico Luca Gasparoli CD preferen2ally inhibits the herg1b isoform (comparison with E 4031)
34 CD preferen2ally blocks herg1b isoform also in leukemia cells FLG 29.1 Cells IC µm
35 CD is synergic with Fludarabine on apoptosis of MEC1 cells (CLL) on MSC
36 Less harmful compounds can be developed which block herg1 channels in cancer cells.
37 Acknowledgements: Dr.Andrea BeccheUniversity of Milano Bicocca Prof.Enzo Wanke
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