Cytotoxicity, intracellular distribution and uptake of doxorubicin and doxorubicin coupled to cell-penetrating peptides in different cell lines: a comparative study.
One of the major obstacles which are opposed to the success of anticancer treatment is the cell resistance that generally develops after administration of commonly used drugs. In this study, we try to overcome the tumour cell resistance of doxorubicin (Dox) by developing a cell-penetrating peptide (CPP)-anticancer drug conjugate in aim to enhance its intracellular delivery and that its therapeutic effects. For this purpose, two cell-penetrating peptides, penetratin (pene) and tat, derived from the HIV-1 TAT protein, were chemically conjugated to Dox. The cytotoxicity, intracellular distribution and uptake were accessed in CHO cells (Chinese Hamster Ovarian carcinoma cells), HUVEC (Human Umbilical Vein Endothelial Cells), differentiated NG108.15 neuronal cell and breast cancer cells MCF7drug-sensitive or MDA-MB 231 drug-resistant cell lines. The conjugates showed different cell killing activity and intracellular distribution pattern by comparison to Dox as assessed respectively by MTT-based colorimetric cellular cytotoxicity assay, confocal fluorescence microscopy and FACS analysis. After treatment with 3 microM with Dox-CPPs for 2h, pene increase the Dox cytotoxicity by 7.19-fold in CHO cells, by 11.53-fold in HUVEC cells and by 4.87-fold in MDA-MB 231 cells. However, cytotoxicity was decreased in NG108.15 cells and MCF7. Our CPPs-Dox conjugate proves the validity of CPPs for the cytoplasmic delivery of therapeutically useful molecules and also a valuable strategy to overcome drug resistance.
Aroui
Sonia
S
Unité 05/UR/09-09, Mécanismes Moléculaires et Pathologies, Faculté de Médecine de Monastir, 5019 Monastir, Tunisie, Tunisia. sonia_aroui2002@yahoo.fr
Brahim
Souhir
S
Waard
Michel De
MD
Kenani
Abderraouf
A
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D001692:Biological Transport; D016466:CHO Cells; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides; D006224:Cricetinae; D003412:Cricetulus; D004317:Doxorubicin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; D010446:Peptide Fragments; D054322:tat Gene Products, Human Immunodeficiency Virus; C422951:tat peptide (48-60), Human immunodeficiency virus 1; D004317:Doxorubicin; C414409:penetratin