Platinum (IV)-fatty acid conjugates overcome inherently and acquired Cisplatin resistant cancer cell lines: an in-vitro study

BMC Cancer

Research Article

Yousef Najajreh¹  Rami Salem¹  Hazem Khamaisie²  Einav Ratzon²  Jamal Mahajna³  Martin Ruthardt⁴ 

[1] Anticancer Drugs Research Lab, Faculty of Pharmacy, Al-Quds University, P.O. Box 20002, Jerusalem, Abu-Dies, Palestinian Authority;Cancer Drug Discovery Program, Migal, Galilee Research Institute, P.O. Box 831, 11016, Kiryat Shmona, Israel;Cancer Drug Discovery Program, Migal, Galilee Research Institute, P.O. Box 831, 11016, Kiryat Shmona, Israel;The Department of Nutritional Sciences, Tel Hai College, Kiryat Shmona, Israel;Medizinische Klinik II/Abtl. Hämatologie, Klinikum der Johann Wolfgang Goethe Universität, Theodor-Stern Kai 7, 60590, Frankfurt, Germany;

关键词: Platinum (IV);    Cisplatin;    Ovarian cancer;    Resistance;    Copper transporter (Ctr1);   

DOI  :  10.1186/s12885-016-2182-8

 received in 2015-07-28, accepted in 2016-02-16,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundPlatinum-based drugs are used as cancer chemotherapeutics for the last 40 years. However, drug resistance and nephrotoxicity are the major limitations of the use of platinum-based compounds in cancer therapy. Platinum (IV) complexes are believed to act as platinum prodrugs and are able to overcome some of platinum (II) limitations.MethodsA number of previously sensitized platinum (IV) complexes were evaluated for their anti-cancer activity by monitoring ability to affect proliferation, clonigenicity and apoptosis induction of Cisplatin sensitive and resistant cancer cells. In addition, the uptake of Cisplatin and the platinum (IV) derivatives to Cisplatin sensitive and resistant cancer cells was monitored.ResultsThe bis-octanoatoplatinum (IV) complex (RJY13), a Cisplatin derivative with octanoate as axial ligand, exhibited strong anti-proliferative effect on the Cisplatin resistant and sensitive ovarian cells, A2780cisR and A2780, respectively. Moreover, RJY13 exhibited good activity in inhibiting clonigenicity of both cells. Anti-proliferative activity of RJY13 was mediated by induction of apoptosis. Interestingly, a bis-lauratopaltinum (IV) complex (RJY6) was highly potent in inhibiting clonigenicity of both Cisplatin sensitive and Cisplatin resistant cells, however, exhibited reduced activity in assays that utilize cells growing in two dimensional (2D) conditions. The uptake of Cisplatin was reduced by 30 % in A2780 in which the copper transporter-1 (Ctr1) was silenced. Moreover, uptake of RJY6 was marginally dependent on Ctr1, while uptake of RJY13 was Ctr1-independent.ConclusionsOur data demonstrated the potential of platinum (IV) prodrugs in overcoming acquired and inherited drug resistance in cancer cell lines. Moreover, our data demonstrated that the uptake of Cisplatin is partially dependent on Ctr1 transporter, while uptake of RJY6 is marginally dependent on Ctr1 and RJY13 is Ctr1-independent. In addition, our data illustrated the therapeutic potential of platinum (IV) prodrugs in cancer therapy.

【 授权许可】

CC BY   
© Ratzon et al. 2016