New Pyrimido-Indole Compound CD-160130 Preferentially Inhibits the K<sub>V</sub>11.1B Isoform and Produces Antileukemic Effects without Cardiotoxicity

Gasparoli, Luca; D’Amico, Massimo; Masselli, Marika; Pillozzi, Serena; Caves, Rachel E.; Khuwaileh, Rawan; Tiedke, Wolfgang; Mugridge, Kenneth G.; Pratesi, Alessandro; Mitcheson, John S.; Basso, Giuseppe; Becchetti, Andrea; Arcangeli, Annarosa

doi:10.1124/mol.114.094920

Cited by 27 publications

(31 citation statements)

References 45 publications

(77 reference statements)

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“…31,43,54,78 Major limitation of hERG1-based tumor therapy in humans is the potential cardiotoxicity that many hERG1 blockers exert. However, a promising first-in-class compound to attempt oncologic therapy without cardiotoxicity, based on targeting the Kv11.1 subunit of the hERG1 channel, has been recently reported, 79 thus supporting the targeting strategy exploited in our study.…”

Section: Discussionsupporting

confidence: 51%

Targeted polyethylene glycol gold nanoparticles for the treatment of pancreatic cancer: from synthesis to proof-of-concept in vitro studies

Spadavecchia¹,

Movia²,

Moore³

et al. 2016

IJN

167

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International audienceThe main objective of this study was to optimize and characterize a drug delivery carrier for doxorubicin, intended to be intravenously administered, capable of improving the therapeutic index of the chemotherapeutic agent itself, and aimed at the treatment of pancreatic cancer. In light of this goal, we report a robust one-step method for the synthesis of dicarboxylic acid-terminated polyethylene glycol (PEG)-gold nanoparticles (AuNPs) and doxorubicin-loaded PEG-AuNPs, and their further antibody targeting (anti-Kv11.1 polyclonal antibody [pAb]). In in vitro proof-of-concept studies, we evaluated the influence of the nanocarrier and of the active targeting functionality on the anti-tumor efficacy of doxorubicin, with respect to its half-maximal effective concentration (EC50) and drug-triggered changes in the cell cycle. Our results demonstrated that the therapeutic efficacy of doxorubicin was positively influenced not only by the active targeting exploited through anti-Kv11.1-pAb but also by the drug coupling with a nanometer-sized delivery system, which indeed resulted in a 30-fold decrease of doxorubicin EC50, cell cycle blockage, and drug localization in the cell nuclei. The cell internalization pathway was strongly influenced by the active targeting of the Kv11.1 subunit of the human Ether-à-go-go related gene 1 (hERG1) channel aberrantly expressed on the membrane of pancreatic cancer cells. Targeted PEG-AuNPs were translocated into the lysosomes and were associated to an increased lysosomal function in PANC-1 cells. Additionally, doxorubicin release into an aqueous environment was almost negligible after 7 days, suggesting that drug release from PEG-AuNPs was triggered by enzymatic activity. Although preliminary, data gathered from this study have considerable potential in the application of safe-by-design nano-enabled drug-delivery systems (ie, nanomedicines) for the treatment of pancreatic cancer, a disease with a poor prognosis and one of the main current burdens of today’s health care bill of industrialized countries

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Section: Discussionsupporting

confidence: 51%

Targeted polyethylene glycol gold nanoparticles for the treatment of pancreatic cancer: from synthesis to proof-of-concept in vitro studies

Spadavecchia¹,

Movia²,

Moore³

et al. 2016

IJN

167

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“…Importantly, similar effects are also observed in vivo, as blocking K v 11.1 in immunodeficient mice decreases: i) the growth of exogenous human gastric and colon cancer cells, and ii) the bone marrow engraftment and peripheral blood invasion of myeloid or lymphoblastic leukaemia cells (Pillozzi et al, 2011;Crociani et al, 2013;Gasparoli et al, 2014). The above evidence and the observation that K v 11.1 regulates proliferation and apoptosis in other tumors (Arcangeli, 2005;Arcangeli et al, 2009;Jehle et al, 2011) suggest that K v 11.1 may be a potential target for antineoplasticbased therapy, provided that one can avoid the cardiotoxic effects.…”

Section: K V 111 and Tumorssupporting

confidence: 55%

“…What is especially important in the present context is that the long-term in vitro observations indicating that blocking the activity of several channel types impairing cell growth have been recently followed up in vivo. Certain tumors have been found to be sensitive to ion channel blockers, which decrease both tumor growth and invasiveness (Lastraioli et al, 2004;Fiske et al, 2006;Gómez-Varela et al, 2007;Pillozzi et al, 2007Pillozzi et al, ,2011Gasparoli et al, 2014), as well as metastasis (Yildirim et al, 2012;Crociani et al, 2013). Some examples, relative to prostate, colorectal and breast cancers, as well as gliomas and leukemias are shown in Fig.…”

Section: Ion Channel Expression and Functional Role In Cancermentioning

confidence: 97%

Novel perspectives in cancer therapy: Targeting ion channels

Arcangeli

Becchetti

2015

Drug Resistance Updates

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“…The general view is emerging that modulation of ion channel activity in B-CLL cells might be a strategy to pursue for therapeutical purposes [9,12,[47][48][49].…”

Section: Cell Physiolmentioning

confidence: 99%

Biophysical Characterization and Expression Analysis of Kv1.3 Potassium Channel in Primary Human Leukemic B Cells

Szabó

Trentin

Trimarco

et al. 2015

Cell Physiol Biochem

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Background/Aims: Pharmacological inhibition of the potassium channel Kv1.3 has been shown to selectively kill B cells from patients with chronic lymphocytic leukemia (B-CLL). Here we aimed to biophysically characterize and compare Kv1.3 channel activity in B cells isolated either from healthy subjects or patients and investigated the mechanism accounting for the increased protein expression in B-CLL cells. Methods: Kv1.3 activity was measured by patch clamp, while expression of the channel protein was assessed by Western blot and FACS analysis. B-CLL cells were co-cultured with mesenchymal stromal cells (MSC) and Kv1.3 inhibitor-induced apoptosis was assessed. Results: We demonstrate that Kv1.3 is highly expressed and is more active at resting membrane potential in human B-CLL cells than in healthy cells. Channel expression in pathologic cells decreased by the B-RAF kinase inhibitor PLX-4720, while it increased with Doxazosin, an α1-adrenoceptor antagonist. Kv1.3 inhibitors induced death in B-CLL cells also when co-cultured with MSC. Conclusion: Our results contribute to the characterization of B-CLL cells, as it shows that upregulation of Kv1.3 in pathologic B lymphocytes is linked to the oncogenic B-RAF signalling. We also conclude that Kv1.3 inhibitors represent a valuable tool to induce apoptosis of B-CLL cells even in the presence of MSC.

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New Pyrimido-Indole Compound CD-160130 Preferentially Inhibits the K_V11.1B Isoform and Produces Antileukemic Effects without Cardiotoxicity

Cited by 27 publications

References 45 publications

Targeted polyethylene glycol gold nanoparticles for the treatment of pancreatic cancer: from synthesis to proof-of-concept in vitro studies

Targeted polyethylene glycol gold nanoparticles for the treatment of pancreatic cancer: from synthesis to proof-of-concept in vitro studies

Novel perspectives in cancer therapy: Targeting ion channels

Biophysical Characterization and Expression Analysis of Kv1.3 Potassium Channel in Primary Human Leukemic B Cells

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New Pyrimido-Indole Compound CD-160130 Preferentially Inhibits the KV11.1B Isoform and Produces Antileukemic Effects without Cardiotoxicity

Cited by 27 publications

References 45 publications

Targeted polyethylene glycol gold nanoparticles for the treatment of pancreatic cancer: from synthesis to proof-of-concept in vitro studies

Targeted polyethylene glycol gold nanoparticles for the treatment of pancreatic cancer: from synthesis to proof-of-concept in vitro studies

Novel perspectives in cancer therapy: Targeting ion channels

Biophysical Characterization and Expression Analysis of Kv1.3 Potassium Channel in Primary Human Leukemic B Cells

Contact Info

Product

Resources

About

New Pyrimido-Indole Compound CD-160130 Preferentially Inhibits the K_V11.1B Isoform and Produces Antileukemic Effects without Cardiotoxicity