Sorafenib and nitazoxanide disrupt mitochondrial function and inhibit regrowth capacity in three-dimensional models of hepatocellular and colorectal carcinoma
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Sorafenib and nitazoxanide disrupt mitochondrial function and inhibit regrowth capacity in three-dimensional models of hepatocellular and colorectal carcinoma. / Ek, Frida; Blom, Kristin; Selvin, Tove; Rudfeldt, Jakob; Andersson, Claes; Senkowski, Wojciech; Brechot, Christian; Nygren, Peter; Larsson, Rolf; Jarvius, Malin; Fryknäs, Mårten.
I: Scientific Reports, Bind 12, Nr. 1, 8943, 2022.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Sorafenib and nitazoxanide disrupt mitochondrial function and inhibit regrowth capacity in three-dimensional models of hepatocellular and colorectal carcinoma
AU - Ek, Frida
AU - Blom, Kristin
AU - Selvin, Tove
AU - Rudfeldt, Jakob
AU - Andersson, Claes
AU - Senkowski, Wojciech
AU - Brechot, Christian
AU - Nygren, Peter
AU - Larsson, Rolf
AU - Jarvius, Malin
AU - Fryknäs, Mårten
N1 - © 2022. The Author(s).
PY - 2022
Y1 - 2022
N2 - Quiescent cancer cells in malignant tumors can withstand cell-cycle active treatment and cause cancer spread and recurrence. Three-dimensional (3D) cancer cell models have led to the identification of oxidative phosphorylation (OXPHOS) as a context-dependent vulnerability. The limited treatment options for advanced hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC) metastatic to the liver include the multikinase inhibitors sorafenib and regorafenib. Off-target effects of sorafenib and regorafenib are related to OXPHOS inhibition; however the importance of this feature to the effect on tumor cells has not been investigated in 3D models. We began by assessing global transcriptional responses in monolayer cell cultures, then moved on to multicellular tumor spheroids (MCTS) and tumoroids generated from a CRC patient. Cells were treated with chemotherapeutics, kinase inhibitors, and the OXPHOS inhibitors. Cells grown in 3D cultures were sensitive to the OXPHOS inhibitor nitazoxanide, sorafenib, and regorafenib and resistant to other multikinase inhibitors and chemotherapeutic drugs. Furthermore, nitazoxanide and sorafenib reduced viability, regrowth potential and inhibited mitochondrial membrane potential in an additive manner at clinically relevant concentrations. This study demonstrates that the OXPHOS inhibition caused by sorafenib and regorafenib parallels 3D activity and can be further investigated for new combination strategies.
AB - Quiescent cancer cells in malignant tumors can withstand cell-cycle active treatment and cause cancer spread and recurrence. Three-dimensional (3D) cancer cell models have led to the identification of oxidative phosphorylation (OXPHOS) as a context-dependent vulnerability. The limited treatment options for advanced hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC) metastatic to the liver include the multikinase inhibitors sorafenib and regorafenib. Off-target effects of sorafenib and regorafenib are related to OXPHOS inhibition; however the importance of this feature to the effect on tumor cells has not been investigated in 3D models. We began by assessing global transcriptional responses in monolayer cell cultures, then moved on to multicellular tumor spheroids (MCTS) and tumoroids generated from a CRC patient. Cells were treated with chemotherapeutics, kinase inhibitors, and the OXPHOS inhibitors. Cells grown in 3D cultures were sensitive to the OXPHOS inhibitor nitazoxanide, sorafenib, and regorafenib and resistant to other multikinase inhibitors and chemotherapeutic drugs. Furthermore, nitazoxanide and sorafenib reduced viability, regrowth potential and inhibited mitochondrial membrane potential in an additive manner at clinically relevant concentrations. This study demonstrates that the OXPHOS inhibition caused by sorafenib and regorafenib parallels 3D activity and can be further investigated for new combination strategies.
KW - Antineoplastic Agents/pharmacology
KW - Carcinoma, Hepatocellular/pathology
KW - Colorectal Neoplasms/drug therapy
KW - Humans
KW - Liver Neoplasms/pathology
KW - Mitochondria/metabolism
KW - Nitro Compounds
KW - Sorafenib/pharmacology
KW - Thiazoles
U2 - 10.1038/s41598-022-12519-4
DO - 10.1038/s41598-022-12519-4
M3 - Journal article
C2 - 35624293
VL - 12
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 8943
ER -
ID: 310566965