| Cannabinoid-induced targeted facilitated entry of cytotoxic compounds selectively into tumor cells
The ultimate goal of developing an anticancer drug is to target only tumor cells, sparing normal cells. Several approaches are used to emphasize the effect of anticancer drugs on tumor cells. Some of these strategies are tuned to target cancer specific cellular machineries. Others, by using polymeric drug carriers, such as liposomes and nanoparticles, can restrict the delivery of non-specific chemotherapeutics primarily to tumor cells. Here we propose a new strategy for the selective elimination of tumor cells.
We based the development of this strategy on our recent work in which we introduced a novel approach for selective targeting of pain- and itch-related neurons. We have shown that the pore of TRPV1 and TRPA1 channels, members of the TRP channel superfamily and which are selectively expressed by pain- and itch - related neurons, is large enough to allow passage of QX-314, a charged derivative of lidocaine, which is ineffective when applied extracellularly, but blocks sodium channels and consequently neuronal excitability when it gains access to the inside of cells. We have shown that activation of TRPV1 and TRPA1 channels provides a pathway for selective entry of QX-314 into pain and itch sensing neurons and therefore inhibition of pain and itch without effecting non-painful sensory and motor neurons. The various members of the TRP channel family are also either selectively expressed or overexpressed by tumor cells. The collective work of many laboratories showed that these channels play a critical role in tumorogenesis, tumor vascularization and the ability of tumor cells to proliferate and migrate.
In this project we are using cannabidiol-induced activation of TRP channels expressed by hepatocellular carcinoma cells as a cell-specific “natural” drug delivery system for selective targeted ablation of cancer cells. This will be of paramount clinical importance, since it will allow decreasing the therapeutic dose of the drugs and thereby limit their side effects without compromising the efficacy. Our results demonstrate that co-injection of cannabidiol, a known activator of TRP channels, together with cytotoxic agent is sufficient to provide the pathway for cytotoxic drugs to penetrate into tumor cells and selectively kill them. Moreover, we show that cannabidiol, in addition to its facilitative effect on drug entry, has an additive effect on drug accumulation inside the cells, by virtue of its inhibitory effect on specific transporters which play a role in removal cytotoxic drugs from the cells. We demonstrated that previously sub-effective dose of cytotoxic drugs, is sufficient to significantly affect tumor cell viability and proliferation when co-applied with the activator cannabidiol. Such facilitated entry will minimize the off-target effect of cytotoxic drugs and therefore will substantially reduce adverse side effects.
See also: Cancer