Rerouting chlorambucil to mitochondria combats drug deactivation and resistance in cancer cells

Sonali B. Fonseca; Mark P. Pereira; Rida Mourtada; Marcela Gronda; Kristin L. Horton; Rose Hurren; Mark D. Minden; Aaron D. Schimmer; Shana O. Kelley

doi:10.1016/j.chembiol.2011.02.010

Rerouting chlorambucil to mitochondria combats drug deactivation and resistance in cancer cells

Sonali B. Fonseca, Mark P. Pereira, Rida Mourtada, Marcela Gronda, Kristin L. Horton, Rose Hurren, Mark D. Minden, Aaron D. Schimmer, Shana O. Kelley

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

99 Scopus citations

Abstract

The difficulty of accessing the mitochondrial matrix has limited the targeting of therapeutics to this organelle. Here, we report, to our knowledge, the first successful delivery of an active DNA alkylating agent - chlorambucil - to mitochondria, and describe unexpected features that result from rerouting this drug within the cell. Mitochondrial targeting of this agent dramatically potentiates its activity, and promotes apoptotic cell death in a variety of cancer cell lines and patient samples. This retention of activity is observed even in cells with resistance to chlorambucil or disabled apoptotic triggering.

Original language	English (US)
Pages (from-to)	445-453
Number of pages	9
Journal	Chemistry and Biology
Volume	18
Issue number	4
DOIs	https://doi.org/10.1016/j.chembiol.2011.02.010
State	Published - Apr 22 2011
Externally published	Yes

ASJC Scopus subject areas

Drug Discovery
Molecular Medicine
Molecular Biology
Biochemistry
Clinical Biochemistry
Pharmacology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.chembiol.2011.02.010

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@article{7077289fc9124bdf82e347b2a601774c,

title = "Rerouting chlorambucil to mitochondria combats drug deactivation and resistance in cancer cells",

abstract = "The difficulty of accessing the mitochondrial matrix has limited the targeting of therapeutics to this organelle. Here, we report, to our knowledge, the first successful delivery of an active DNA alkylating agent - chlorambucil - to mitochondria, and describe unexpected features that result from rerouting this drug within the cell. Mitochondrial targeting of this agent dramatically potentiates its activity, and promotes apoptotic cell death in a variety of cancer cell lines and patient samples. This retention of activity is observed even in cells with resistance to chlorambucil or disabled apoptotic triggering.",

author = "Fonseca, {Sonali B.} and Pereira, {Mark P.} and Rida Mourtada and Marcela Gronda and Horton, {Kristin L.} and Rose Hurren and Minden, {Mark D.} and Schimmer, {Aaron D.} and Kelley, {Shana O.}",

note = "Funding Information: We gratefully acknowledge the Ontario Institute for Cancer Research (M.D.M.), the Canadian Foundation for Innovation (S.O.K.), and the Terry Fox Foundation Strategic Training Initiative for Excellence in Radiation Research for the 21st Century (M.P.P., R.M.). A.D.S. is a Leukemia and Lymphoma Society Scholar in Clinical Research. Funding for S.B.F. was provided by the NSERC Canada Graduate Scholarship (CGS). ",

year = "2011",

month = apr,

day = "22",

doi = "10.1016/j.chembiol.2011.02.010",

language = "English (US)",

volume = "18",

pages = "445--453",

journal = "Chemistry and Biology",

issn = "1074-5521",

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T1 - Rerouting chlorambucil to mitochondria combats drug deactivation and resistance in cancer cells

AU - Fonseca, Sonali B.

AU - Pereira, Mark P.

AU - Mourtada, Rida

AU - Gronda, Marcela

AU - Horton, Kristin L.

AU - Hurren, Rose

AU - Minden, Mark D.

AU - Schimmer, Aaron D.

AU - Kelley, Shana O.

N1 - Funding Information: We gratefully acknowledge the Ontario Institute for Cancer Research (M.D.M.), the Canadian Foundation for Innovation (S.O.K.), and the Terry Fox Foundation Strategic Training Initiative for Excellence in Radiation Research for the 21st Century (M.P.P., R.M.). A.D.S. is a Leukemia and Lymphoma Society Scholar in Clinical Research. Funding for S.B.F. was provided by the NSERC Canada Graduate Scholarship (CGS).

PY - 2011/4/22

Y1 - 2011/4/22

N2 - The difficulty of accessing the mitochondrial matrix has limited the targeting of therapeutics to this organelle. Here, we report, to our knowledge, the first successful delivery of an active DNA alkylating agent - chlorambucil - to mitochondria, and describe unexpected features that result from rerouting this drug within the cell. Mitochondrial targeting of this agent dramatically potentiates its activity, and promotes apoptotic cell death in a variety of cancer cell lines and patient samples. This retention of activity is observed even in cells with resistance to chlorambucil or disabled apoptotic triggering.

AB - The difficulty of accessing the mitochondrial matrix has limited the targeting of therapeutics to this organelle. Here, we report, to our knowledge, the first successful delivery of an active DNA alkylating agent - chlorambucil - to mitochondria, and describe unexpected features that result from rerouting this drug within the cell. Mitochondrial targeting of this agent dramatically potentiates its activity, and promotes apoptotic cell death in a variety of cancer cell lines and patient samples. This retention of activity is observed even in cells with resistance to chlorambucil or disabled apoptotic triggering.

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SN - 1074-5521

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JO - Chemistry and Biology

JF - Chemistry and Biology

IS - 4

ER -

Rerouting chlorambucil to mitochondria combats drug deactivation and resistance in cancer cells

Abstract

ASJC Scopus subject areas

UN SDGs

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