Preclinical study of a Kv11.1 potassium channel activator as antineoplastic approach for breast cancer

Daniela F. Fukushiro-Lopes; Alexandra D. Hegel; Vidhya Rao; Debra Wyatt; Andrew Baker; Eun Kyoung Breuer; Clodia Osipo; Jeremiah J. Zartman; Miranda Burnette; Simon Kaja; Dimitrios Kouzoukas; Sarah Burris; W. Keith Jones; Saverio Gentile

doi:10.18632/oncotarget.22925

Preclinical study of a Kv11.1 potassium channel activator as antineoplastic approach for breast cancer

Daniela F. Fukushiro-Lopes, Alexandra D. Hegel, Vidhya Rao, Debra Wyatt, Andrew Baker, Eun Kyoung Breuer, Clodia Osipo, Jeremiah J. Zartman, Miranda Burnette, Simon Kaja, Dimitrios Kouzoukas, Sarah Burris, W. Keith Jones, Saverio Gentile

Research output: Contribution to journal › Article › peer-review

35 Scopus citations

Abstract

Potassium ion (K⁺) channels have been recently found to play a critical role in cancer biology. Despite that pharmacologic manipulation of ion channels is recognized as an important therapeutic approach, very little is known about the effects of targeting of K+ channels in cancer. In this study, we demonstrate that use of the Kv11.1 K⁺ channel activator NS1643 inhibits tumor growth in an in vivo model of breast cancer. Tumors exposed to NS1643 had reduced levels of proliferation markers, high expression levels of senescence markers, increased production of ROS and DNA damage compared to tumors of untreated mice. Importantly, mice treated with NS1643 did not exhibit significant cardiac dysfunction. In conclusion, pharmacological stimulation of Kv11.1 activity produced arrested TNBC-derived tumor growth by generating DNA damage and senescence without significant side effects. We propose that use of Kv11.1 channels activators could be considered as a possible pharmacological strategy against breast tumors.

Original language	English (US)
Pages (from-to)	3321-3337
Number of pages	17
Journal	Oncotarget
Volume	9
Issue number	3
DOIs	https://doi.org/10.18632/oncotarget.22925
State	Published - 2018
Externally published	Yes

Keywords

Activator
Cancer therapy
DNA damage
Ion channels
Senescence

ASJC Scopus subject areas

Oncology

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10.18632/oncotarget.22925

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Fukushiro-Lopes, D. F., Hegel, A. D., Rao, V., Wyatt, D., Baker, A., Breuer, E. K., Osipo, C., Zartman, J. J., Burnette, M., Kaja, S., Kouzoukas, D., Burris, S., Keith Jones, W., & Gentile, S. (2018). Preclinical study of a Kv11.1 potassium channel activator as antineoplastic approach for breast cancer. Oncotarget, 9(3), 3321-3337. https://doi.org/10.18632/oncotarget.22925

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title = "Preclinical study of a Kv11.1 potassium channel activator as antineoplastic approach for breast cancer",

abstract = "Potassium ion (K+) channels have been recently found to play a critical role in cancer biology. Despite that pharmacologic manipulation of ion channels is recognized as an important therapeutic approach, very little is known about the effects of targeting of K+ channels in cancer. In this study, we demonstrate that use of the Kv11.1 K+ channel activator NS1643 inhibits tumor growth in an in vivo model of breast cancer. Tumors exposed to NS1643 had reduced levels of proliferation markers, high expression levels of senescence markers, increased production of ROS and DNA damage compared to tumors of untreated mice. Importantly, mice treated with NS1643 did not exhibit significant cardiac dysfunction. In conclusion, pharmacological stimulation of Kv11.1 activity produced arrested TNBC-derived tumor growth by generating DNA damage and senescence without significant side effects. We propose that use of Kv11.1 channels activators could be considered as a possible pharmacological strategy against breast tumors.",

keywords = "Activator, Cancer therapy, DNA damage, Ion channels, Senescence",

author = "Fukushiro-Lopes, {Daniela F.} and Hegel, {Alexandra D.} and Vidhya Rao and Debra Wyatt and Andrew Baker and Breuer, {Eun Kyoung} and Clodia Osipo and Zartman, {Jeremiah J.} and Miranda Burnette and Simon Kaja and Dimitrios Kouzoukas and Sarah Burris and {Keith Jones}, W. and Saverio Gentile",

note = "Funding Information: MB and JJZ were supported in part by American Cancer Research Grant #IRG-14-195-01. Publisher Copyright: {\textcopyright} Fukushiro-Lopes et al.",

year = "2018",

doi = "10.18632/oncotarget.22925",

language = "English (US)",

volume = "9",

pages = "3321--3337",

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T1 - Preclinical study of a Kv11.1 potassium channel activator as antineoplastic approach for breast cancer

AU - Fukushiro-Lopes, Daniela F.

AU - Hegel, Alexandra D.

AU - Rao, Vidhya

AU - Wyatt, Debra

AU - Baker, Andrew

AU - Breuer, Eun Kyoung

AU - Osipo, Clodia

AU - Zartman, Jeremiah J.

AU - Burnette, Miranda

AU - Kaja, Simon

AU - Kouzoukas, Dimitrios

AU - Burris, Sarah

AU - Keith Jones, W.

AU - Gentile, Saverio

N1 - Funding Information: MB and JJZ were supported in part by American Cancer Research Grant #IRG-14-195-01. Publisher Copyright: © Fukushiro-Lopes et al.

PY - 2018

Y1 - 2018

N2 - Potassium ion (K+) channels have been recently found to play a critical role in cancer biology. Despite that pharmacologic manipulation of ion channels is recognized as an important therapeutic approach, very little is known about the effects of targeting of K+ channels in cancer. In this study, we demonstrate that use of the Kv11.1 K+ channel activator NS1643 inhibits tumor growth in an in vivo model of breast cancer. Tumors exposed to NS1643 had reduced levels of proliferation markers, high expression levels of senescence markers, increased production of ROS and DNA damage compared to tumors of untreated mice. Importantly, mice treated with NS1643 did not exhibit significant cardiac dysfunction. In conclusion, pharmacological stimulation of Kv11.1 activity produced arrested TNBC-derived tumor growth by generating DNA damage and senescence without significant side effects. We propose that use of Kv11.1 channels activators could be considered as a possible pharmacological strategy against breast tumors.

AB - Potassium ion (K+) channels have been recently found to play a critical role in cancer biology. Despite that pharmacologic manipulation of ion channels is recognized as an important therapeutic approach, very little is known about the effects of targeting of K+ channels in cancer. In this study, we demonstrate that use of the Kv11.1 K+ channel activator NS1643 inhibits tumor growth in an in vivo model of breast cancer. Tumors exposed to NS1643 had reduced levels of proliferation markers, high expression levels of senescence markers, increased production of ROS and DNA damage compared to tumors of untreated mice. Importantly, mice treated with NS1643 did not exhibit significant cardiac dysfunction. In conclusion, pharmacological stimulation of Kv11.1 activity produced arrested TNBC-derived tumor growth by generating DNA damage and senescence without significant side effects. We propose that use of Kv11.1 channels activators could be considered as a possible pharmacological strategy against breast tumors.

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Preclinical study of a Kv11.1 potassium channel activator as antineoplastic approach for breast cancer

Abstract

Keywords

ASJC Scopus subject areas

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