PP Mechanisms of Action as an Anti-Cancer Agent: History
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Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Christopher W. Schultz
,
Avinoam Nevler

Pyrvinium, a lipophilic cation belonging to the cyanine dye family, has been used in the clinic as a safe and effective anthelminthic for over 70 years. Its structure, similar to some polyaminopyrimidines and mitochondrial-targeting peptoids, has been linked with mitochondrial localization and targeting. Unsurprisingly for a small-molecule compound, pyrvinium pamoate (PP) has been shown to act through multiple mechanisms. The majority of the published articles assessing PP specifically as an anticancer therapeutic have focused on two main MOA, which appear to be at the root of PP action: inhibition of the WNT pathway and inhibition of mitochondrial function.

  • pyrvinium
  • cancer
  • mitochondria
  • drug repurposing

1. WNT Signaling

The WNT/β-catenin signaling pathway is one of the essential pathways regulating the cell differentiation, development, and self-renewal of stem cells. As such, it has also been tightly associated with key events in cancer initiation and progression [1][2][3][4][5][6][7][8][9][10]. In 2010, Thorne et al. [11] found that PP inhibited the WNT signaling pathway at low nanomolar concentrations (in vitro and in vivo) in Xenopus laevis and in human colon cancer cells. They determined that PP bound and activated Casein kinase 1α (CK1α), thereby promoting the degradation of β-catenin, the primary effector of the WNT pathway. Supporting this work, Cui et al. [12], Li et al. [13], and Shen et al. [14] have all subsequently demonstrated that PP targeted the WNT pathway in a CK1α-dependent fashion in various cancer models. However, other studies have contested this mechanism and have suggested that PP acts through the upstream inhibition of the Akt/GSK-3β/β-catenin pathway [15][16].
In addition to pre-clinical studies assessing PP as a monotherapy in colon cancer [17][18], PP was found to act as a chemoprotective agent in the formation of intestinal polyps in an APCmin mouse model, presumably through its inhibition of the WNT pathway [19]. PP was also shown to synergize with the KRAS inhibitor salirasib in a WNT-dependent manner, describing a potentially actionable targeted combination of PP and salirasib in KRAS-driven colon cancers [20].

2. Mitochondrial Inhibition

Like many other cyanine dyes, and similar to mitochondrial-targeting peptoids [21], pyrvinium is a lipophilic cation, which allows it to preferentially target the mitochondria. Historically, the activity of PP as an anti-mitochondrial agent was linked to its efficacy at inhibiting protozoa including the plasmodium species associated with malaria [22][23][24]. To an extent, this was also linked to pyrvinium’s ability to inhibit various fungi [25][26]. From an evolutionary standpoint, the endosymbiotic theory holds that mitochondria were generated in a progenitor eukaryotic cell through endosymbiosis and that mitochondria maintain many similarities with bacteria [27]. Unsurprisingly, multiple antibiotics have displayed significant efficacy against cancer cells through inhibiting the mitochondria [28][29][30][31]. PP, interestingly, was first found to be an anti-mitochondrial agent, and only subsequently found to show significant activity against bacteria including Mycobacterium tuberculosis [22][32][33].
Multiple studies have implicated mitochondrial inhibition as a key factor in the activity of PP against cancer cells. Compelling support for this MOA lies in the facts that PP activity is increased in nutrient-poor microenvironments [34][35], and that mitochondrial DNA-depleted cell lines have shown significant resistance to PP therapy [36][37]. Several mechanisms of action have been suggested to explain the PP-dependent mitochondrial inhibition. A frequently proposed mechanism revolves around the inhibition of the mitochondrial respiratory complex I, with data showing PP doses of 0.1–1μM significantly inhibited complex I enzymatic activity, resulting in decreased ATP production and the increased production of reactive oxygen species (ROS) [37][38]. Tomitsuka et al. [39] have also shown that PP treatment of cancer cells (Panc-1, DLD-1, HepG2) resulted in the inhibition of the NADH–fumarate reductase system, a system primarily associated with cancer metabolism in dually hypoxic and hypoglycemic conditions, and increased activity of complex II (succinate–ubiquinone reductase).
In a recent study by Schultz et al. [35], a new MOA for PP-mediated mitochondrial inhibition was proposed. In the study, PP was shown to result in the significant depletion of mitochondrially encoded RNA transcripts and the downregulation of electron transport chain proteins. Here it was found that PP, similar to other G-quadruplex binding agents, bound G-quadruplex structures, which are over-represented in mitochondrial DNA and profoundly inhibited global mitochondrial transcription [40][41].
Overall, it is likely that all of these actions can occur with PP treatment. Acute treatment of PP will lead to the inhibition of complex I and the electron transport chain in normoxic conditions and the inhibition of the NADH–fumarate reductase system in hypoxic conditions. However, prolonged treatment will cause more global dysregulation of mitochondrial function through the inhibition of mitochondrial transcription in all conditions.

3. Tumor Stemness

An important feature of tumor cell population self-renewal and survival after chemotherapy treatment is through a specialized sub-population of cancer-initiating cells or “cancer stem cells” [42][43][44]. Interestingly, a common MOA attributed to the anti-cancer effect of PP is the inhibition of cancer stem cells. Xu et al. [45] found that PP targeted tumor-initiating cells and impaired tumor self-renewal in breast cancer. In vivo PP treatment slowed tumor growth, decreased lung metastasis, and synergized with radiotherapy. Zhang et al. have shown the inhibitory effects of pyrvinium pamoate (PP) on lung cancer stem cells in vitro [46][47]. Similar studies have found PP to inhibit tumor stemness in multiple cancer types including melanoma, leukemia, glioblastoma, and cancers of the prostate, pancreas, lung, ovary, and breast [36][48][49][50]. Interestingly, the inhibition of cancer stem and initiating cells appears to be derivative of PP’s inhibition of the WNT [48] and mitochondrial pathways [36][49], both of which are specifically critical for cancer initiating and stem cells. Venugopal et al. showed that CD133high and CD133-overexpressed cells displayed increased WNT signaling and were highly sensitive to PP treatment [48]. However, Xiang et al. [36] noted that although pyrvinium treatment showed selectivity to blast-phase chronic myeloid leukemia CD34+ progenitor cells, CK1α depletion did not affect PP sensitivity and WNT overexpression failed to rescue these cells. Instead, PP was shown to mainly accumulate in the mitochondria and the creation of chronic myeloid leukemia (CML) ρ0 cells that lacked mitochondrial DNA caused resistance to PP. Similar references to a mitochondrial-driven targeting of cancer stem cells were made by Datta et al. [49] in their assessment of PP in glioma-like stem cells. Recently, Dattilo et al. [51] showed that PP targeted triple-negative breast cancer stem cells through the inhibition of lipid anabolism, resulting in the increased death of cancer stem cells. Additionally, it seems as though the inhibition of stemness is not limited to cancer, but is also apparent in dysplastic tissues—as was described by Min et al. [52], showing that PP can inhibit Trop2+/CD133+/CD166+ dysplastic gastric mucosa stem cells in mouse and human organoids.
Interestingly, PP has been shown to promote wound repair, inhibit fibrotic tissue development [53][54][55], and protect from ischemic injury and promote healing [56][57]. This appears to be directly related to improved stem cell survival and the inhibition of inappropriate lineage commitment [58], which appears contradictory to the known efficacy of PP against cancer progenitor and stem cells [36][46][50]. However, it has been demonstrated that PP preferentially targets cancer progenitor cells compared to non-malignant normal progenitor cells [36]. This is likely due to the altered metabolism and reliance of cancer stem cells on mitochondrial-related pathways including oxidative phosphorylation [36][59] and lipid metabolism [51][60].

4. ELAVL1/HuR Inhibition

ELAVL1/HuR is an RNA-binding protein that has been shown to be an important post-transcriptional regulator of many cancer-associated pro-survival genes such as VEGF, WEE1, and IDH1 [61][62][63][64][65]. Its mechanism, at least in part, is associated with the nucleocytoplasmic translocation and stabilization of 3′UTR of target mRNA transcripts [66][67]. Pyrvinium pamoate has been described by Goa et al. [68] as a functional HuR inhibitor that shifts the HuR cytoplasmic/nuclear equilibrium in favor of the nuclear import of HuR by blocking HuR nucleo-cytoplasmic translocation through inhibiting the checkpoint kinase1/cyclin-dependent kinase 1 pathway and activating the AMP-activated kinase/importin α1 cascade.
It is important to note that a published byproduct of PP’s inhibition of mitochondrial function and ATP production is a relative increase in AMP and in AMP-related signaling, which raises the possibility that PP is not a direct activator of AMP-activated kinase/importin α1. Similarly, other studies have shown that the CRISPR knockout of HuR failed to rescue cancer cells from PP-induced cytotoxicity [35].

5. Androgen Receptor Inhibition

In 2008, PP was identified as a novel androgen inhibitor based on a high-throughput FRET screen [69]. It was shown to be a potent anti-prostate cancer agent that inhibited the function of androgen receptor (AR) splice variants, potentially through interaction with the AR DNA-binding domain (DBD), and the inhibition of several splicing factors (such as DDX17) [70][71][72]. Its DNA-binding domain interaction was thought to occur as a result of binding at the interface of the DBD dimer and the minor groove of the AR response element [72]. However, as noted by Li et al., PP treatment was toxic to LNCaP cells and AR-negative PC3 cells even at concentrations lower than the AR IC50, which is suggestive that PP’s anti prostate cancer efficacy was mediated through a non-AR-related mechanism [73].

6. Unfolded Protein Response

Cells, and cancer cells in particular, undergo physiological processes that require a high rate of protein production and degradation. During protein production, unfolded or misfolded proteins can accumulate in the endoplasmic reticulum, resulting in increased cellular stress (i.e., ER stress). ER stress can also be increased upon physiological, environmental, or pharmacological insults. The unfolded protein response (UPR) is an adaptive cellular survival mechanism that regulates the cell’s handling of ER stress. In routine function, the ER stress signaling activates the unfolded protein response to reduce the volume of unfolded protein load and to help maintain normal cell function and metabolism [74]. However, chronic or extreme ER stress can trigger cell death by apoptosis and has been linked to many diseases such as cancer, diabetes, and neurodegenerative disorders [75][76][77][78][79].
Yu et al. [80] have shown that after hypoglycemia induced UPR, PP suppressed the transcriptional activation of UPR-regulated apoptosis and autophagy targets including XBP-1 and ATF-4 [80][81] along with inhibiting the induction of UPR transcription factors GRP78 (HSPA5) and GRP94 (HSP90B1). Interestingly PP did not inhibit the UPR when it was initiated by non-metabolic agents [80], potentially indicating that the inhibition of the UPR is secondary to the mitochondrial and metabolic dysregulation associated with PP treatment. Another aspect that is yet to be assessed is the impact of PP on the mitochondrial unfolded protein response (UPRmt), a crucial pathway for the maintenance of mitochondrial homeostasis [82].

7. Attenuation of Hedgehog Signaling

The hedgehog (SHH) signaling pathway is one of the key developmental pathways regulating cell proliferation, differentiation, and stem cell renewal [83]. Not surprisingly, the SHH pathway has been shown to play a key role in multiple cancer types [84]. Li et al. [85] were the first to describe PP as an inhibitor of the SHH pathway, and determined that PP treatment decreased the expression of downstream targets of the SHH pathway including Patched1 and Gli-family transcription factors in vitro and in vivo. Subsequently, El-Derhany et al. [86] noted that PP caused the dual inhibition of the WNT and SHH pathways. However, as a specific SHH target has yet to be identified, it is possible that due to the reciprocal coregulation between the WNT and SHH pathways that the inhibition of SHH is secondary to PP’s effects on the WNT pathway [87].

8. Inhibition of PD-1/PDL-1 Interaction

Immunotherapies, and PD-1/PDL-1 inhibitors specifically, have revolutionized many fields of cancer therapy. PDL-1 (CD274)/PD1 (CD279) is an important modulatory/inhibitory immune checkpoint mechanism, utilized by some cancers to target and suppress the adaptive immune response [88]. Upon the binding of PDL-1, a transmembrane ligand, to its immune cell receptor PD-1 (which is highly expressed in activated T-cells), an inhibitory signaling cascade results in decreased T-cell proliferation, the induction of apoptosis in antigen-specific T-cells, and the inhibition of apoptosis in regulatory T-cells [88][89]. In a recent paper by Fattakhova et al. [90], a focused structure- and ligand-based drug library screen was employed that identified PP as an effective blocker of the PD-1/PDL-1 interaction. Of note, they found the IC50 for PP inhibition of PD-1/PDL-1 to be ∼30 μM, which is a promising starting point for PP to serve as a lead compound for the development of more potent inhibitors. However, since PP inhibits mitochondria, the WNT pathway and cancer cell viability at concentrations that are orders of magnitude lower than the noted IC50 for PD-1/PDL-1 inhibition, this immunoactive mechanism is likely not a relevant MOA for PP.

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10123249

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