Endoplasmic reticulum-targeting doxorubicin: a new tool effective against doxorubicin-resistant osteosarcoma

Autor: Barbara Rolando, Marilù Fanelli, Ilaria Buondonno, Elisa Tavanti, Alberto Gasco, Konstantin Chegaev, Massimo Serra, Chiara Riganti, Claudia Maria Hattinger, Elena Gazzano, Joanna Kopecka, Roberta Fruttero
Rok vydání: 2018
Předmět:
Endoplasmic reticulum stress
Endoplasmic reticulum-associated protein degradation
H 2 S-releasing doxorubicin
Osteosarcoma
P-glycoprotein
Antibiotics
Antineoplastic
Apoptosis
Cell Survival
DNA Damage
Doxorubicin
Drug Resistance
Neoplasm
Endoplasmic Reticulum
Humans
Immunoblotting
Inhibitory Concentration 50
Polymerase Chain Reaction
Drug Delivery Systems
Molecular Medicine
Molecular Biology
Pharmacology
Cellular and Molecular Neuroscience
Cell Biology
Drug Resistance
Protein degradation
Endoplasmic-reticulum-associated protein degradation
03 medical and health sciences
Antibiotics
polycyclic compounds
medicine
Caspase
0303 health sciences
biology
Chemistry
Endoplasmic reticulum
030302 biochemistry & molecular biology
medicine.disease
Antineoplastic
Cancer research
biology.protein
Neoplasm
medicine.drug
Zdroj: Cellular and Molecular Life Sciences. 76:609-625
ISSN: 1420-9071
1420-682X
DOI: 10.1007/s00018-018-2967-9
Popis: Doxorubicin is one of the most effective drugs for the first-line treatment of high-grade osteosarcoma. Several studies have demonstrated that the major cause for doxorubicin resistance in osteosarcoma is the increased expression of the drug efflux transporter ABCB1/P-glycoprotein (Pgp). We recently identified a library of H2S-releasing doxorubicins (Sdox) that were more effective than doxorubicin against resistant osteosarcoma cells. Here we investigated the molecular mechanisms of the higher efficacy of Sdox in human osteosarcoma cells with increasing resistance to doxorubicin. Differently from doxorubicin, Sdox preferentially accumulated within the endoplasmic reticulum (ER), and its accumulation was only modestly reduced in Pgp-expressing osteosarcoma cells. The increase in doxorubicin resistance was paralleled by the progressive down-regulation of genes of ER-associated protein degradation/ER-quality control (ERAD/ERQC), two processes that remove misfolded proteins and protect cell from ER stress-triggered apoptosis. Sdox, that sulfhydrated ER-associated proteins and promoted their subsequent ubiquitination, up-regulated ERAD/ERQC genes. This up-regulation, however, was insufficient to protect cells, since Sdox activated ER stress-dependent apoptotic pathways, e.g., the C/EBP-β LIP/CHOP/PUMA/caspases 12-7-3 axis. Sdox also promoted the sulfhydration of Pgp that was subsequently ubiquitinated: this process further enhanced Sdox retention and toxicity in resistant cells. Our work suggests that Sdox overcomes doxorubicin resistance in osteosarcoma cells by at least two mechanisms: it induces the degradation of Pgp following its sulfhydration and produces a huge misfolding of ER-associated proteins, triggering ER-dependent apoptosis. Sdox may represent the prototype of innovative anthracyclines, effective against doxorubicin-resistant/Pgp-expressing osteosarcoma cells by perturbing the ER functions.
Databáze: OpenAIRE
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