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Eur J Med Chem. 2019 Jun 1;171:104-115. doi: 10.1016/j.ejmech.2019.03.031. Epub 2019 Mar 18.

Synthesis and anti-cancer evaluation of folic acid-peptide- paclitaxel conjugates for addressing drug resistance.

Author information

1
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
2
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Department of Biochemistry and Molecular Biology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, PR China.
3
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
4
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: qianhai24@163.com.

Abstract

The drug resistance and the poor water solubility are major limitations of paclitaxel (PTX) of based chemotherapy. To conquer the two problems, targeting folate (FA) receptor PTX-lytic peptides conjugates were synthesized and evaluated. Compared with PTX, FA-P3-PTX and FA-P7-PTX displayed significantly enhanced cell toxicity in many cancer cells, particularly drug resistant cancer cells MCF-7/PTX. FA-P7-PTX possessed stronger effect on cell toxicity (IC50 = 2.92 ± 0.2 μM), membrane disrupting activity and pro-apoptosis in MCF-7/PTX cells than FA-P3-PTX. Further investigation displayed that the anti-cancer mechanisms of FA-P3-PTX and FA-P7-PTX might be a mitochondrial impairment and caspase-3-dependent apoptotic cell death. Furthermore, the in vivo antitumor efficacy study confirmed that FA-P7-PTX performed more stronger potency in inhibition of tumors growth than PTX. The study demonstrated that conjugate FA-P7-PTX with superior properties for antineoplastic activity, which makes it a promising potential candidate for drug-resistant cancer therapy.

KEYWORDS:

Apoptosis; Conjugates of paclitaxel; Drug resistance; Folate receptor targeted; Lytic peptides; Membranolytic; Paclitaxel

PMID:
30913525
DOI:
10.1016/j.ejmech.2019.03.031
[Indexed for MEDLINE]

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