2-APB and CBD-mediated targeting of charged cytotoxic compounds into tumor cells suggests the involvement of TRPV2 channels

Hagit Neumann-Raizel, Asaf Shilo, Shaya Lev, Maxim Mogilevsky, Ben Katz, David Shneor, Yoav D. Shaul, Andreas Leffler, Alberto Gabizon, Rotem Karni, Alik Honigman, Alexander M. Binshtok*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Targeted delivery of therapeutic compounds to particular cell types such that they only affect the target cells is of great clinical importance since it can minimize undesired side effects. For example, typical chemotherapeutic treatments used in the treatment of neoplastic disorders are cytotoxic not only to cancer cells but also to most normal cells when exposed to a critical concentration of the compound. As such, many chemotherapeutics exhibit severe side effects, often prohibiting their effective use in the treatment of cancer. Here, we describe a new means for facilitated delivery of a clinically used chemotherapy compound' doxorubicin, into hepatocellular carcinoma cell line (BNL1 ME). We demonstrate that these cells express a large pore, cation non-selective transient receptor potential (TRP) channel V2. We utilized this channel to shuttle doxorubicin into BNL1 ME cells. We show that co-application of either cannabidiol (CBD) or 2-APB, the activators of TRPV2 channels, together with doxorubicin leads to significantly higher accumulation of doxorubicin in BNL1 ME cells than in BNL1 ME cells that were exposed to doxorubicin alone. Moreover, we demonstrate that sub-effective doses of doxorubicin when co-applied with either 2-APB or CBD lead to a significant decrease in the number of living BNL1 ME cell and BNL1 ME cell colonies in comparison to application of doxorubicin alone. Finally, we demonstrate that the doxorubicin-mediated cell death is significantly more potent, requiring an order of magnitude lower dose, when co-applied with CBD than with 2-APB. We suggest that CBD may have a dual effect in promoting doxorubicin-mediated cell death by facilitating the entry of doxorubicin via TRPV2 channels and preventing its clearance from the cells by inhibiting P-glycoprotein ATPase transporter. Collectively, these results provide a foundation for the use of large pore cation-non selective channels as “natural” drug delivery systems for targeting specific cell types.

Original languageAmerican English
Article number1198
JournalFrontiers in Pharmacology
Volume10
DOIs
StatePublished - 2019

Bibliographical note

Funding Information:
Support is gratefully acknowledged from the Deutsch-Israelische Projectkooperation program of the Deutsche Forschungsgemeinschaft (DIP) grant agreement BI 1665/1-1ZI1172/12-1 (HN-R, BK, SL, and AB); the Israeli Science Foundation - grant agreement 1470/17 (HN-R, BK, SL and AB);

Funding Information:
Support is gratefully acknowledged from the Deutsch-Israelische Projectkooperation program of the Deutsche Forschungsgemeinschaft (DIP) grant agreement BI 1665/1-1ZI1172/12-1 (HN-R, BK, SL, and AB); the Israeli Science Foundation - grant agreement 1470/17 (HN-R, BK, SL and AB); Rosetrees Foundation A1777 and M139 (AB) and the Marie Curie International Reintegration Grant and Rosetrees Trust (AB).

Publisher Copyright:
Copyright © 2019 Neumann-Raizel, Shilo, Lev, Mogilevsky, Katz, Shneor, Shaul, Leffler, Gabizon, Karni, Honigman and Binshtok. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Keywords

  • 2-APB
  • BNL1 ME cells
  • Cannabidiol
  • Doxorubicin
  • Hepatocellular carcinoma
  • Membrane permeation
  • TRPV2 channels
  • Targeted delivery

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