‘Et tu, inhibitor?’: the potential for HIV inhibitors to prime P-gp-mediated chemoresistance in cancer

“Thus, by coalescing the established information of P-gp-driven MDR in cancer and recent reports demonstrating the ability of nonchemotherapeutic inhibitors of HIV to increase P-gp activity in both cancerous and noncancerous tissue, future direction should be considered in determining which commonly administered drug regimens have the potential to prime cancer-susceptible tissues to be more resistant to chemotherapies that are P-gp substrates.”

and implicated in clonal selection-mediated chemoresistance [6][7][8][9]. In either case, P-gp induction plays a critical role in creating a chemoresistant phenotype in cancer cells, ultimately providing motivation for determining how to best mitigate the counteracting mechanisms of P-gp in cancer treatment.
One of the conventional directions taken when investigating P-gp-mediated resistance is understanding which chemotherapies induce this increased state of P-gp activity and determining how certain P-gp substrate chemotherapies could be co-administered rationally with compounds that counteract P-gp activity. Based on this direction, several classes of drug compounds have been identified as potential inhibitors of P-gp. Interestingly, one class of compounds identified to influence P-gp activity are established tyrosine-kinase inhibitors (TKIs) used in several cancer therapy regimens. While several studies report acquired resistance of single-agent TKI treatment being mediated through P-gp, several reports also reveal the ability for TKIs to counteract P-gp-mediated chemoresistance and increase the cytotoxic effects of P-gp substrate chemotherapies [10]. Such examples of TKIs demonstrating this inhibitory capability have been the BCR/ABL-targeting nilotonib [11], the VEGFR-targeting apatanib [12] and the EGFR-targeting lapatinib, gefitinib and erlonitib [13]. Determining how certain TKIs interact with P-gp could provide a double-edged therapeutic benefit against malignant progression based on both the canonical actions of TKIs disrupting the extracellular signaling cascade utilized for cancer growth as well as its noncanonical action of increasing intracellular accumulation of chemotherapies through the blockade of P-gp efflux action.
Nevertheless, while great efforts have been placed into better understanding the means for which to overcome P-gp resistance, little is still understood regarding the factors that make certain tumor populations more inclined to acquire a P-gp chemoresistant phenotype. Traditionally, studies that have investigated this mechanistic question employ a limited scope regarding the therapeutic agents that can increase P-gp activity in cancers, with most studies focusing on chemotherapies specifically and how they mediate an increase in P-gp expression and activity. However, with a reported count of over 300 compounds that are predicted to directly interact with P-gp, it can be reasonably posited that cancer chemotherapies are not the only class of pharmaceutical compounds that could manipulate the activity of P-gp in cancer cells [2,3]. This idea of nonchemotherapy-driven induction of cancer chemoresistance was first broached by a study from Lucia et al. who reported induced upregulation of P-gp expression in Kaposi's sarcoma cells through prolonged exposure of known HIV protease inhibitors including indinavir, nelfinavir and ritonavir. This upregulation in P-gp expression, seen at both the transcriptional and translational levels, was coupled with an increase in both doxorubicin and paclitaxel resistance in each of the prolonged HIV protease inhibitor-treated SLK Kaposi's sarcoma cell lines as well as an increased efflux of the fluorescent dye rhodamine 123, which is used to measure P-gp-mediated efflux. These results are quite intriguing based on the notion that the nonchemotherapeutic P-gp substrates of these HIV protease inhibitors could induce a chemotherapy-resistant phenotype in vitro. Interestingly, the means in which the HIV protease inhibitors induce these phenotypes are perhaps different from the means in which P-gp substrate chemotherapies induce a P-gp based on the observation that doxorubicin could increase P-gp expression within 72 h, whereas prolonged HIV protease inhibitor treatment took approximately 6 months to demonstrate prevalent expression of P-gp. These results suggest that while P-gp substrate chemotherapies like doxorubicin or paclitaxel can induce acute expression of P-gp, prolonged exposure of nonchemotherapy P-gp substrates like HIV protease inhibitors perhaps provide a selective pressure where cells with higher P-gp levels would be given a selective advantage during cancer propagation and/or tissue renewal [ P-gp through prolonged treatment of nonchemotherapeutic compounds could prime certain tissue types to be less sensitive to chemotherapy treatments if cancer were to arise within the respective tissue. This phenomenon could very well be feasible specifically for colon tissue based on the dynamics of colon cancer development and the opportunity for drug compounds like HIV inhibitors to establish increased expression of P-gp. Thus, by coalescing the established information of P-gp-driven MDR in cancer and recent reports demonstrating the ability of nonchemotherapeutic inhibitors of HIV to increase P-gp activity in both cancerous and noncancerous tissue, future direction should be considered in determining which commonly administered drug regimens have the potential to prime cancersusceptible tissues to be more resistant to chemotherapies that are P-gp substrates. This question is especially prevalent based on recent studies that report a significant increase in prescription use among the adult population in the USA as well a significant increase in medication use among adults 65 years or older in England [16,17]. Thus, investigating commonly prescribed medications and their potential to selectively increase P-gp activity in tissue that are susceptible to cancer initiation, tumorigenic progression and chemoresistance should be intentionally considered.

Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.

Open access
This work is licensed under the Creative Commons Attribution 4.0 License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/