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Cellular and Molecular Life Sciences

, Volume 76, Issue 3, pp 609–625 | Cite as

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

  • Ilaria Buondonno
  • Elena Gazzano
  • Elisa Tavanti
  • Konstantin Chegaev
  • Joanna Kopecka
  • Marilù Fanelli
  • Barbara Rolando
  • Roberta Fruttero
  • Alberto Gasco
  • Claudia Hattinger
  • Massimo Serra
  • Chiara RigantiEmail author
Original Article
  • 153 Downloads

Abstract

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.

Keywords

Osteosarcoma P-glycoprotein H2S-releasing doxorubicin Endoplasmic reticulum-associated protein degradation Endoplasmic reticulum stress 

Abbreviations

dox

Doxorubicin

ABCB1/Pgp

ATP binding cassette B1/P-glycoprotein

H2S

Hydrogen sulfide

ROS

Reactive oxygen species

Sdox

H2S-releasing doxorubicin

FBS

Fetal bovine serum

MFI

Mean fluorescence intensity

LDH

Lactate dehydrogenase

FITC

Fluorescein isothiocyanate

PI

Propidium iodide

RLU

Relative luminescence units

DAPI

4′,6-Diamidino-2-phenylindole dihydrochloride

GFP

Green fluorescence protein

ER

Endoplasmic reticulum

EDEM1

ER degradation enhancing α-mannosidase like protein 1

UGGT1

UDP-glucose glycoprotein glucosyltransferase 1

SEC62

SEC62 homolog/preprotein translocation factor

VCP

Valosin-containing protein

GRP78/BiP

Glucose-regulated protein 78/binding immunoglobulin protein

IRE1α

Inositol requiring kinase-1α

XBP1

X-box binding protein 1

PERK

Protein kinase-like endoplasmic reticulum kinase

eIF2α

Eukariotic initiation factor-2α

ATF4

Activating transcription factor 4

ATF6

Activating transcription factor 6

C/EBP-β

CCAAT-enhancer-binding protein-β

CHOP/GADD153

C/EBP homologous protein/growth arrest and DNA damage 153

TRB3

Tribbles homolog 3

PUMA

p53 up-regulated modulator of apoptosis

TBP

TATA box binding protein antibodies

DTT

Dithiothreitol

RFU

Relative fluorescence units

UPR

Unfolded protein response

ERAD

Endoplasmic reticulum-associated protein degradation

ERQC

Endoplasmic reticulum quality control

Notes

Acknowledgements

The work was supported by Italian Association for Cancer Research (IG15232 to CR); Italian Ministry of University and Research (RBFR12SOQ1 to C.R.); Istituto Ortopedico Rizzoli I.R.C.C.S. (5 x mille contributions to the Rizzoli Institute). We are grateful to Dr. Maria Alessandra Contino, Department of Pharmacy, University of Bari “Aldo Moro”, Bari, Italy, for the fruitful discussion, to Dr. Maria Pia Patrizio, Istituto Ortopedico Rizzoli I.R.C.C.S., for the help for the IC50 calculations and to Mr. Costanzo Costamagna, Department of Oncology, University of Torino, for the technical assistance.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

18_2018_2967_MOESM1_ESM.tif (7.4 mb)
Supplementary material 1 (TIFF 7569 kb) Supplementary Fig. 1 (Online Resource 1) Representative dot plots of apoptotic/necrotic cells. Doxorubicin-sensitive U-2OS and Saos-2 human osteosarcoma cell lines and their resistant variants (DX30, DX100 and DX580) were incubated 24 h with drug-free medium, 5 µM doxorubicin (dox) or H2S-releasing doxorubicin (Sdox), then the percentage of cells positively stained for Annexin V-FITC or propidium iodide (PI) was measured by flow cytometry in duplicates. Dot plots are representative of 1 out of 3 experiments
18_2018_2967_MOESM2_ESM.docx (17 kb)
Supplementary material 2 (DOCX 17 kb)
18_2018_2967_MOESM3_ESM.tif (1.9 mb)
Supplementary material 3 (TIFF 1895 kb) Supplementary Fig. 2 (Online Resource 3) Dose–response effect of doxorubicin and H2S-releasing doxorubicin on cell viability. Human doxorubicin-sensitive U-2OS cells and Saos-2 cells and their resistant sublines DX580 were incubated for 72 h with increasing concentrations (from 10 nM to 0.5 mM) of doxorubicin (dox) or H2S-releasing doxorubicin (Sdox). Cell viability measured by a chemiluminescence-based assay in quadruplicates. Data are mean ± SD (n = 6 independent experiments)
18_2018_2967_MOESM4_ESM.tif (1.2 mb)
Supplementary material 4 (TIFF 1229 kb) Supplementary Fig. 3 (Online Resource 4). Effects of doxorubicin and H2S-releasing doxorubicin on non-transformed cells. Human osteoblasts, human fibroblasts and rat H9c2 cardiomyocytes were grown in drug-free medium (ctrl) or in medium containing 5 µM doxorubicin (dox) or H2S-releasing doxorubicin (Sdox) for 24 h (panels a, c, e) or 72 h (panels b, d, f). a, c, e Extracellular release of LDH measured spectrophotometrically in triplicates. Data are mean ± SD (n = 3 independent experiments). *p < 0.001 for treated vs. untreated cells; °p < 0.001 for Sdox vs. dox. b, d, f Cell viability measured with a chemiluminescence-based method in quadruplicates. Data are mean ± SD (n = 3 independent experiments). *p < 0.002 for treated vs. untreated cells; °p < 0.05 for Sdox vs. dox
18_2018_2967_MOESM5_ESM.tif (1.5 mb)
Supplementary material 5 (TIFF 1530 kb) Supplementary Fig. 4 (Online Resource 5) Effects of verapamil on H2S-releasing doxorubicin accumulation and cytotoxicity. Doxorubicin-sensitive U-2OS human osteosarcoma cell line and its U-2OS/DX580 resistant variant were cultured for 6 h (panels a-b), 24 h (panels c-d) or 72 h (panels e–f) in drug-free medium (ctrl) or in medium containing 5 µM doxorubicin (dox) or H2S-releasing doxorubicin (Sdox), in the absence (-) or presence (+) of 50 µM verapamil (ver). a-b. Intracellular drug accumulation, measured by flow cytometry in duplicates, and expressed as mean fluorescence intensity (MFI). Data are mean ± SD (n = 6 independent experiments). *p < 0.001 for treated vs. untreated cells; °p < 0.001 for verapamil-treated vs. verapamil-untreated cells. c-d Extracellular release of LDH measured spectrophotometrically in triplicates. Data are mean ± SD (n = 4 independent experiments). *p < 0.001 for treated vs. untreated cells; °p < 0.01 for verapamil-treated vs. verapamil-untreated cells. e–f Cell viability measured with a chemiluminescence-based method in quadruplicates. Data are mean ± SD (n = 3 independent experiments). *p < 0.001 for treated vs. untreated cells; °p < 0.001 for verapamil-treated vs. verapamil-untreated cells
18_2018_2967_MOESM6_ESM.tif (4.5 mb)
Supplementary material 6 (TIFF 4630 kb) Supplementary Fig. 5 (Online Resource 6) Early intracellular localization of doxorubicin within sensitive osteosarcoma cells. U-2OS cells were incubated for 24 h with the GFP-KDEL-calreticulin expression vector to label endoplasmic reticulum (ER), then treated with 5 µM doxorubicin (dox) for 10 min, 20 min, 30 min, 1 h, 3 h, 6 h, 24 h. The intracellular localization of the drug was analyzed by fluorescence microscopy. Magnification: 63 × objective lens (1.42 numerical aperture); 10 × ocular lens Bar: 7.5 μm. The micrographs are representative of the dox localization after 20 min, corresponding to the time point with the highest accumulation within the ER, and are representative of 3 experiments with similar results
18_2018_2967_MOESM7_ESM.docx (32 kb)
Supplementary material 7 (DOCX 31 kb)
18_2018_2967_MOESM8_ESM.tif (1.2 mb)
Supplementary material 8 (TIFF 1184 kb) Supplementary Fig. 6 (Online Resource 8) Expression of ERAD/ERQC and UPR-related genes in doxorubicin-sensitive and doxorubicin-resistant osteosarcoma cells. a-c Hitmap of unfolded protein response (UPR)-related genes, cell death/survival related genes, ER-associated degradation/endoplasmic reticulum quality control (ERAD/ERQC)-related genes in U-2OS/DX30, U-2OS/DX100 and U-2OS/DX580 cells. The figure reports genes up-or down-regulated at least twofold, in at least one cell line, compared to untreated U-2OS cells (n = 6 independent experiments). The expression of each gene in U-2OS cells was considered 1 (not shown). The whole list of genes analyzed is reported in Supplementary Table 2 (Online Resource 7)
18_2018_2967_MOESM9_ESM.docx (28 kb)
Supplementary material 9 (DOCX 28 kb)
18_2018_2967_MOESM10_ESM.docx (29 kb)
Supplementary material 10 (DOCX 29 kb)
18_2018_2967_MOESM11_ESM.tif (338 kb)
Supplementary material 11 (TIFF 338 kb) Supplementary Fig. 7 (Online Resource 11) Expression of genes related to cell death and survival in doxorubicin-sensitive and doxorubicin-resistant osteosarcoma cells. Hitmap of genes related to cell death/survival in U-2OS and U-2OS/DX580 cells, after 24 h treatment with drug-free medium, 5 µM doxorubicin (dox) or H2S-releasing doxorubicin (Sdox). The figure reports genes up-or down-regulated at least twofold, in at least one cell line, compared to untreated U-2OS cells (n = 6 independent experiments). The expression of each gene in U-2OS cells was considered 1 (not shown). The whole list of genes analyzed is reported in Supplementary Tables 3-4 (Online Resources 9-10)

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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Ilaria Buondonno
    • 1
  • Elena Gazzano
    • 1
  • Elisa Tavanti
    • 2
  • Konstantin Chegaev
    • 3
  • Joanna Kopecka
    • 1
  • Marilù Fanelli
    • 2
  • Barbara Rolando
    • 3
  • Roberta Fruttero
    • 3
  • Alberto Gasco
    • 3
  • Claudia Hattinger
    • 2
  • Massimo Serra
    • 2
  • Chiara Riganti
    • 1
    Email author
  1. 1.Department of OncologyUniversity of TorinoTorinoItaly
  2. 2.Laboratory of Experimental Oncology, Pharmacogenomics and Pharmacogenetics Research UnitOrthopaedic Rizzoli Institute I.R.C.C.SBolognaItaly
  3. 3.Department of Drug Science and TechnologyUniversity of TorinoTorinoItaly

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