Doxorubicin (dox) is one of the first-line drug in osteosarcoma treatment but its effectiveness is limited by the efflux pump P-glycoprotein (Pgp) and by the onset of cardiotoxicity. We previously demonstrated that synthetic doxs conjugated with a H2S-releasing moiety (Sdox) were less cardiotoxic and more effective than dox against Pgp-overexpressing osteosarcoma cells. In order to increase the active delivery to tumor cells, we produced hyaluronic acid (HA)-conjugated liposomes containing Sdox (HA-Lsdox), exploiting the abundance of the HA receptor CD44 in osteosarcoma. HA-Lsdox showed favorable drug-release profile and higher toxicity in vitro and in vivo than dox or the FDA-approved liposomal dox Caelyx® against Pgp-overexpressing osteosarcoma, displaying the same cardiotoxicity profile of Caelyx®. Differently from dox, HA-Lsdox delivered the drug within the endoplasmic reticulum (ER), inducing protein sulfhydration and ubiquitination, and activating a ER stress pro-apoptotic response mediated by CHOP. HA-Lsdox also sulfhydrated the nascent Pgp in the ER, reducing its activity. We propose HA-Lsdox as an innovative tool noteworthy to be tested in Pgp-overexpressing patients, who are frequently less responsive to standard treatments in which dox is one of the most important drugs.

Hyaluronated liposomes containing H2S-releasing doxorubicin are effective against P-glycoprotein-positive/doxorubicin-resistant osteosarcoma cells and xenografts

Gazzano E.;Buondonno I.;Marengo A.;Rolando B.;Chegaev K.;Kopecka J.;SAPONARA, SIMONA;Sorge M.;Gasco A.;Fruttero R.;Brancaccio M.;Stella B.;Fattal E.;Arpicco S.;Riganti C.
2019

Abstract

Doxorubicin (dox) is one of the first-line drug in osteosarcoma treatment but its effectiveness is limited by the efflux pump P-glycoprotein (Pgp) and by the onset of cardiotoxicity. We previously demonstrated that synthetic doxs conjugated with a H2S-releasing moiety (Sdox) were less cardiotoxic and more effective than dox against Pgp-overexpressing osteosarcoma cells. In order to increase the active delivery to tumor cells, we produced hyaluronic acid (HA)-conjugated liposomes containing Sdox (HA-Lsdox), exploiting the abundance of the HA receptor CD44 in osteosarcoma. HA-Lsdox showed favorable drug-release profile and higher toxicity in vitro and in vivo than dox or the FDA-approved liposomal dox Caelyx® against Pgp-overexpressing osteosarcoma, displaying the same cardiotoxicity profile of Caelyx®. Differently from dox, HA-Lsdox delivered the drug within the endoplasmic reticulum (ER), inducing protein sulfhydration and ubiquitination, and activating a ER stress pro-apoptotic response mediated by CHOP. HA-Lsdox also sulfhydrated the nascent Pgp in the ER, reducing its activity. We propose HA-Lsdox as an innovative tool noteworthy to be tested in Pgp-overexpressing patients, who are frequently less responsive to standard treatments in which dox is one of the most important drugs.
456
29
39
www.elsevier.com/locate/canlet
Endoplasmic reticulum stress; Liposomal doxorubicin; Osteosarcoma; P-glycoprotein; Protein sulfhydration
Gazzano E.; Buondonno I.; Marengo A.; Rolando B.; Chegaev K.; Kopecka J.; Saponara S.; Sorge M.; Hattinger C.M.; Gasco A.; Fruttero R.; Brancaccio M.; Serra M.; Stella B.; Fattal E.; Arpicco S.; Riganti C.
File in questo prodotto:
File Dimensione Formato  
Gazzano, Cancer lett MS and SI 2019.pdf

Accesso riservato

Descrizione: Gazzano, Cancer Lett 2019
Tipo di file: PDF EDITORIALE
Dimensione 4.32 MB
Formato Adobe PDF
4.32 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Gazzano_Cancer Letter submitted.pdf

Accesso aperto

Descrizione: Gazzano, preprint open access 2019 Cancer lett
Tipo di file: PREPRINT (PRIMA BOZZA)
Dimensione 765.26 kB
Formato Adobe PDF
765.26 kB Adobe PDF Visualizza/Apri
Hyaluronated liposomes containing H2S-releasing doxorubicin are effectiveagainst P-glycoprotein-positive.pdf

Accesso riservato

Tipo di file: PDF EDITORIALE
Dimensione 2.36 MB
Formato Adobe PDF
2.36 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1712386
Citazioni
  • ???jsp.display-item.citation.pmc??? 11
  • Scopus 25
  • ???jsp.display-item.citation.isi??? 24
social impact