TY - JOUR
T1 - Perturbation of Copper Homeostasis Sensitizes Cancer Cells to Elevated Temperature
AU - Scutigliani, Enzo M.
AU - van Hattum, Jons
AU - Lobo-Cerna, Fernando
AU - Kruyswijk, Joanne
AU - Myrcha, Maja
AU - Dekkers, Frederique E. G. A.
AU - Hoebe, Ron A.
AU - Edwards, Finn
AU - Oppelaar, Jetta J.
AU - Vogt, Liffert
AU - Bootsma, Sanne
AU - Bijlsma, Maarten F.
AU - Picavet, Daisy I.
AU - Crezee, Johannes
AU - Oddens, Jorg R.
AU - de Reijke, Theo M.
AU - Krawczyk, Przemek M.
N1 - Publisher Copyright: © 2023 by the authors.
PY - 2024/1/1
Y1 - 2024/1/1
N2 - Temporary elevation of tumor temperature, also known as hyperthermia, is a safe and well-tolerated treatment modality. The efficacy of hyperthermia can be improved by efficient thermosensitizers, and various candidate drugs, including inhibitors of the heat stress response, have been explored in vitro and in animal models, but clinically relevant thermosensitizers are lacking. Here, we employ unbiased in silico approaches to uncover new mechanisms and compounds that could be leveraged to increase the thermosensitivity of cancer cells. We then focus on elesclomol, a well-performing compound, which amplifies cell killing by hyperthermia by 5- to 20-fold in cell lines and outperforms clinically applied chemotherapy when combined with hyperthermia in vitro. Surprisingly, our findings suggest that the thermosensitizing effects of elesclomol are independent of its previously reported modes of action but depend on copper shuttling. Importantly, we show that, like elesclomol, multiple other copper shuttlers can thermosensitize, suggesting that disturbing copper homeostasis could be a general strategy for improving the efficacy of hyperthermia.
AB - Temporary elevation of tumor temperature, also known as hyperthermia, is a safe and well-tolerated treatment modality. The efficacy of hyperthermia can be improved by efficient thermosensitizers, and various candidate drugs, including inhibitors of the heat stress response, have been explored in vitro and in animal models, but clinically relevant thermosensitizers are lacking. Here, we employ unbiased in silico approaches to uncover new mechanisms and compounds that could be leveraged to increase the thermosensitivity of cancer cells. We then focus on elesclomol, a well-performing compound, which amplifies cell killing by hyperthermia by 5- to 20-fold in cell lines and outperforms clinically applied chemotherapy when combined with hyperthermia in vitro. Surprisingly, our findings suggest that the thermosensitizing effects of elesclomol are independent of its previously reported modes of action but depend on copper shuttling. Importantly, we show that, like elesclomol, multiple other copper shuttlers can thermosensitize, suggesting that disturbing copper homeostasis could be a general strategy for improving the efficacy of hyperthermia.
KW - cancer
KW - copper
KW - elesclomol
KW - heat stress
KW - hyperthermia
UR - http://www.scopus.com/inward/record.url?scp=85182246488&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/ijms25010423
DO - https://doi.org/10.3390/ijms25010423
M3 - Article
C2 - 38203594
SN - 1661-6596
VL - 25
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 1
M1 - 423
ER -