Role of Organic Cation Transporter 2 in Autophagy Induced by Platinum Derivatives.

Sara Ahmed Eltayeb,Katrin Beul,Giuliano Ciarimboli,Giovana Seno Di Marco,Vivien Barz

doi:10.3390/ijms23031090

Sara Ahmed Eltayeb, Katrin Beul + Show 3 more

Open Access

https://doi.org/10.3390/ijms23031090

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Abstract

The human organic cation transporter 2 (hOCT2) mediates renal and neuronal cellular cisplatin and oxaliplatin uptake, and therefore plays a significant role in the development of side effects associated with these chemotherapeutic drugs. Autophagy is induced by cisplatin and oxaliplatin treatment and is believed to promote cell survival under stressful conditions. We examined in vitro the role of hOCT2 on autophagy induced by cisplatin and oxaliplatin. We also explored the effect of autophagy on toxicities of these platinum derivatives. Our results indicate that autophagy, measured as LC3 II accumulation and reduction in p62 expression level, is induced in response to cisplatin and oxaliplatin in HEK293-hOCT2 but not in wild-type HEK293 cells. Furthermore, inhibition of autophagy is associated with higher toxicity of platinum derivatives, and starvation was found to offer protection against cisplatin-associated toxicity. In conclusion, activation of autophagy could be a potential strategy to protect against unwanted toxicities induced by treatment with platinum derivatives.

Highlights

Cisplatin ((SP-4-2)-diammindichloridoplatin(II), CDDP) and oxaliplatin ([(1R,2R)cyclohexane-1,2-diamine](ethanedioato-O,O’)platinum(II), OX) are platinum (Pt) derivatives which play an important role in the treatment of epithelial malignancies such as lung, head, neck, ovarian, bladder and testicular cancer [1,2,3,4]
We investigated the relationship between human organic cation transporter 2 (hOCT2) and autophagy flux induced by CDDP and OX
Since starvation is a strong triggering factor of autophagy [19,28], we investigated whether light chain 3 (LC3) I is modified to LC3 II in response to starvation

Summary

Introduction

Cisplatin ((SP-4-2)-diammindichloridoplatin(II), CDDP) and oxaliplatin ([(1R,2R)cyclohexane-1,2-diamine](ethanedioato-O,O’)platinum(II), OX) are platinum (Pt) derivatives which play an important role in the treatment of epithelial malignancies such as lung, head, neck, ovarian, bladder and testicular cancer [1,2,3,4]. These chemotherapeutic agents are known to target DNA, forming intrastrand and interstrand cross links, which subsequently lead to DNA damage and cellular apoptosis [3]. Growing evidence [8,9,10] suggests that these side effects are attributed to the interaction between Pt agents and organic cation transporters (OCTs). Pharmacological targeting of OCT2 could be a promising strategy in preventing side effects associated with cancer therapy with Pt derivatives [11]

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