Guiding TRAIL to cancer cells through Kv10.1 potassium channel overcomes resistance to doxorubicin.

Franziska Hartung,Luis A Pardo

doi:10.1007/s00249-016-1149-7

Abstract

Resisting cell death is one of the hallmarks of cancer, and represents a common problem resulting in ineffective cancer therapy. To overcome resistance to apoptosis, we designed an antibody-based therapy strategy using Kv10.1 as a target. Kv10.1 is a voltage-gated potassium channel, which has been identified as a tumor marker several years ago. The agent consists of a Kv10.1-specific single-chain antibody fused to the soluble tumor necrosis factor-related apoptosis-inducing ligand (scFv62-TRAIL). We combined scFv62-TRAIL with different chemotherapeutic drugs, all of which failed to induce apoptosis when used alone. In the combination, we could overcome the resistance and selectively induce apoptosis. Among the drugs, doxorubicin showed the most promising effect. Additionally, we observed improved efficacy by pre-treating the cells with doxorubicin before scFv62-TRAIL application. Expression analysis of the TRAIL death receptors suggests a doxorubicin-induced increase in the abundance of receptors as the mechanism for sensitization. Furthermore, we confirmed the anti-tumor effect and efficacy of our combination strategy in vivo in SCID mice bearing subcutaneous tumors. In conclusion, we propose a novel strategy to overcome resistance to chemotherapy in cancer cells. Doxorubicin and scFv62-TRAIL reciprocally sensitize the cells to each other, specifically in Kv10.1-positive tumor cells.

Highlights

Resistance against chemotherapeutic agents is still a major obstacle for effective cancer therapy (Krishna and Mayer 2000), and the search for alternative therapeutic strategies and cancer-specific targets to efficiently treat cancer is stronger than ever (Volm and Efferth 2015)
The selectivity for Kv10.1 expressing cancer cells and the potent apoptosis induction of our fusion construct was already demonstrated with prostate cancer cells
The highly metastatic and Kv10.1-positive cancer cell line MDA-MB435S is described to be resistant against many chemotherapeutic agents and to TRAIL-induced apoptosis (Grosse-Wilde and Kemp 2008; Ortiz-Ferrón et al 2008)

Summary

Introduction

Resistance against chemotherapeutic agents is still a major obstacle for effective cancer therapy (Krishna and Mayer 2000), and the search for alternative therapeutic strategies and cancer-specific targets to efficiently treat cancer is stronger than ever (Volm and Efferth 2015). TRAIL, the tumor necrosis factor-related apoptosis-inducing ligand, is a promising candidate for cancer treatment and its soluble form is already in clinical trials, with limited success (Cheah et al 2015). TRAIL is expressed on the surface of immune cells and binds to five different receptors. TRAILR1 and TRAIL-R2, induce caspase activation and apoptotic cell death after ligand binding. TRAIL-R3 and TRAIL-R4 are decoy receptors, expressed on the cell surface but lacking functional intracellular death domains (LeBlanc and Ashkenazi 2003). TRAIL-R5, known as osteoprotegerin, is a soluble receptor and does not induce apoptosis (Emery et al 1998). Compared to other death receptors, e.g., TNF or CD95, TRAIL is well tolerated, has low side effects and shows potent anti-tumor effect (Ashkenazi et al 1999)

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Conclusion