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.
Highlights
Inhibition of specific enzymes, formation of protein complexes, or modification of transcription factors' activity affects either cell state, such as excitability or activity, or even cell fate, by modulating survival, growth, division, etc
It has been shown that urothelial carcinoma cells (Caprodossi et al, 2008; Mizuno et al, 2014), human leukemic cells (Pottosin et al, 2015), prostate cancer cells (Monet et al, 2010), esophagus squamous cell carcinoma cells (Zhou et al, 2014), and hepatocellular carcinoma cells (Liu et al, 2010) overexpress TRP vanilloid subtype 2 channel (TRPV2) channels
We sought to examine whether a pore of TRPV2 channels expressed by a murine model of hepatocellular carcinoma cells [BNL1 ME (Kuriyama et al, 1999; Tatsumi et al, 1999; Ogunwobi and Liu, 2011)] could be used to shuttle doxorubicin into these cells selectively
Summary
Inhibition of specific enzymes, formation of protein complexes, or modification of transcription factors' activity affects either cell state, such as excitability or activity, or even cell fate, by modulating survival, growth, division, etc. We target otherwise membrane-impermeable hydrophilic chemotherapy agents into cancer cells via the pore of cation non-selective transient receptor potential (TRP) channels, expressed in a differential manner by many types of tumor cells. We and others have suggested that this method could be used for targeted delivery of charged cytotoxic compounds into tumor cells that express large cationic channels (Bean et al, 2007; Santoni and Farfariello, 2011; Nabissi et al, 2013) We tested this hypothesis by targeting mouse hepatocellular carcinoma BNL1 ME cells with a clinically used chemotherapy drug, doxorubicin. The usage of high doses, promotes drug off-target side effects
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