Overcoming Intrinsic Doxorubicin Resistance in Melanoma by Anti-Angiogenic and Anti-Metastatic Effects of Liposomal Prednisolone Phosphate on Tumor Microenvironment

被引:21
作者
Licarete, Emilia [1 ,2 ]
Rauca, Valentin Florian [1 ,3 ]
Luput, Lavinia [1 ,3 ]
Drotar, Denise [1 ]
Stejerean, Ioana [1 ]
Patras, Laura [1 ,3 ]
Dume, Bogdan [1 ]
Toma, Vlad Alexandru [1 ,4 ,5 ]
Porfire, Alina [6 ]
Gherman, Claudia [7 ]
Sesarman, Alina [1 ,3 ]
Banciu, Manuela [1 ,3 ]
机构
[1] Babes Bolyai Univ, Fac Biol & Geol, Dept Mol Biol & Biotechnol, Cluj Napoca 400006, Romania
[2] Babes Bolyai Univ, Ctr Mol Biol, Inst Interdisciplinary Res Bionanosci, Cluj Napoca 400271, Romania
[3] Babes Bolyai Univ, Ctr Syst Biol Biodivers & Bioresources, Fac Biol & Geol, Cluj Napoca 400006, Romania
[4] Inst Biol Res, Cluj Napoca 400015, Romania
[5] Natl Inst Res & Dev Isotop & Mol Technol, Cluj Napoca 400293, Romania
[6] Iuliu Hatieganu Univ Med & Pharm, Dept Pharmaceut Technol & Biopharmaceut, Fac Pharm, Cluj Napoca 400012, Romania
[7] Oncol Inst Prof Dr Ion Chiricuta, Dept Funct Genom & Expt Pathol, Cluj Napoca 400015, Romania
关键词
angiogenesis; combined therapy; liposomes; melanoma; tumor associated macrophages; GROWTH-FACTOR EXPRESSION; ANTITUMOR-ACTIVITY; PHASE-II; IN-VIVO; MACROPHAGES; CELLS; CANCER; MMP-2; CHEMOTHERAPY; PROTEIN-1;
D O I
10.3390/ijms21082968
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Regardless of recent progress, melanoma is very difficult to treat, mainly due to the drug resistance modulated by tumor cells as well as by the tumor microenvironment (TME). Among the immune cells recruited at the tumor site, tumor associated macrophages (TAMs) are the most abundant, promoting important tumorigenic processes: angiogenesis, inflammation and invasiveness. Furthermore, it has been shown that TAMs are involved in mediating the drug resistance of melanoma cells. Thus, in the present study, we used liposomal formulation of prednisolone disodium phosphate (LCL-PLP) to inhibit the protumor function of TAMs with the aim to sensitize the melanoma cells to the cytotoxic drug doxorubicin (DOX) to which human melanoma has intrinsic resistance. Consequently, we evaluated the in vivo effects of the concomitant administration of LCL-PLP and liposomal formulation of DOX (LCL-DOX) on B16.F10 melanoma growth and on the production of key molecular markers for tumor development. Our results demonstrated that the concomitant administration of LCL-PLP and LCL-DOX induced a strong inhibition of tumor growth, primarily by inhibiting TAMs-mediated angiogenesis as well as the tumor production of MMP-2 and AP-1. Moreover, our data suggested that the combined therapy also affected TME as the number of infiltrated macrophages in melanoma microenvironment was reduced significantly.
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页数:19
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