Cross-drug resistance to sunitinib induced by doxorubicin in endothelial cells

Limin Huang (1) , Chaoquan Hu (2) , Mélanie Di Benedetto (3) , Rémi Varin (1) , Jielin Liu (2) , Jian Jin (4) , Li Wang (3) , Jean-Pierre Vannier (5) , Anne Janin (2) , He Lu (6) , Hong Li (7)

1 MERCI - Micro-Environnement et Régulation Cellulaire Intégrée
2 Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique
3 UMR 1165 - Cancer et Transplantation : Physiopathologie et Réponse Thérapeutique
4 GEPEA - Laboratoire de génie des procédés - environnement - agroalimentaire
5 CHU Rouen
6 UMR_S_553 - Hemostase, Endothelium, Angiogenese
7 IoP/CAS - Beijing National Laboratory for Condensed Matter Physics and Institute of Physics

Multiple drug resistance remains an unsolved problem in cancer therapy. A previous study has demonstrated that the chemotherapeutic drug doxorubicin (Dox) induced upregulation of P-glycoprotein in endothelial cells, resulting in a 20-fold increase in drug resistance and reduced efficiency of doxorubicin treatment in a mouse tumor model. In the present study, the cross-resistance and sensitivity of HMECd1 and HMECd2 established cell lines to anti-angiogenic drugs, particularly sunitinib, was explored. The results revealed that Dox treatment induced a significant increase in the breast cancer resistance protein (ABCG2) gene transcription and protein expression. This increase gave rise to a 4-to 5-fold increase in the half maximal inhibitory concentration of the HMECd1 and HMECd2 cells in response to sunitinib treatment in vitro. Functionally, the role of ABCG2 in the resistance to sunitinib was confirmed by the use of the ABCG2 inhibi-tors fumitremorgin C and diethylstilbestrol, which blocked cell resistance. The present study indicates that endothelial cells exhibit cross-resistance between cytotoxic drugs and anti-angiogenic drugs. This suggests that multiple drug resistance induced by chemotherapy in endothelial cells may affect the efficiency of anti-angiogenic drugs.

Domaines: Sciences du Vivant [q-bio]; Biologie cellulaire; Cancer

Limin Huang, Chaoquan Hu, Mélanie Di Benedetto, Rémi Varin, Jielin Liu, et al.. Cross-drug resistance to sunitinib induced by doxorubicin in endothelial cells. Oncology Letters, 2015, 9 (3), pp.1287-1292. ⟨10.3892/ol.2014.2819⟩. ⟨hal-02378497⟩