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Cytotoxic mechanisms of doxorubicin at clinically relevant concentrations in breast cancer cells

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Abstract

Doxorubicin (DOX) is a chemotherapeutic agent frequently used for the treatment of a variety of tumor types, such as breast cancer. Despite the long history of DOX, the mechanistic details of its cytotoxic action remain controversial. Rather than one key mechanism of cytotoxic action, DOX is characterized by multiple mechanisms, such as (1) DNA intercalation and adduct formation, (2) topoisomerase II (TopII) poisoning, (3) the generation of free radicals and oxidative stress, and (4) membrane damage through altered sphingolipid metabolism. Many past reviews of DOX cytotoxicity are based on supraclinical concentrations, and several have addressed the concentration dependence of these mechanisms. In addition, most reviews lack a focus on the time dependence of these processes. We aim to update the concentration and time-dependent trends of DOX mechanisms at representative clinical concentrations. Furthermore, attention is placed on DOX behavior in breast cancer cells due to the frequent use of DOX to treat this disease. This review provides insight into the mechanistic pathway(s) of DOX at levels found within patients and establishes the magnitude of effect for each mechanism.

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Abbreviations

aSMase:

Acid sphingomyelinase

CDK:

Cyclin-dependent kinase

DHE:

Dihydroethidium

DHR:

Dihydrorhodamine 123

DOX:

Doxorubicin

DSB:

Double-stranded break

dsDNA:

Double-stranded DNA

FLT:

3’Deoxy-3’-[18F]fluorothymidine

GCS:

Glucosylceramide synthase

GPx:

Glutathione peroxidase

IM:

Internal membrane

LMP:

Lysosome membrane permeabilization

LPX:

Lipid peroxidation

MDR:

Multidrug resistance

MMP:

Mitochondrial membrane permeability

MPTP:

Mitochondrial permeability transition pore

PUFA:

Polyunsaturated fatty acids

ROS:

Reactive oxygen species

S1P:

Sphingosine-1-phosphate

SK:

Sphingosine kinase

SM:

Sphingomyelin

SMase:

Sphingomyelinase

SOD:

Superoxide dismutase

SR:

Sarcoplasmic reticulum

SSB:

Single-stranded break

TopII:

Topoisomerase II

TNBC:

Triple-negative breast cancer

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Acknowledgements

The authors gratefully acknowledge support from the Agnes Varis Trust for Leadership and Women’s Health (REN) and the Milton Lev Memorial Faculty Research Fund (CMO).

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Agnes Varis Trust for Leadership and Women’s Health. Milton Lev Memorial Faculty Research Fund.

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  1. Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, 600 South 43rd Street, Philadelphia, PA, 19101-4495, USA

    Rachel E. Nicoletto & Clyde M. Ofner III

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Nicoletto, R.E., Ofner, C.M. Cytotoxic mechanisms of doxorubicin at clinically relevant concentrations in breast cancer cells. Cancer Chemother Pharmacol 89, 285–311 (2022). https://doi.org/10.1007/s00280-022-04400-y

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