Abstract
Pyrvinium pamoate, a widely-used anthelmintic agent, reportedly exhibits significant anti-tumor effects in several cancers. However, the efficacy and mechanisms of pyrvinium against myeloid leukemia remain unclear. The growth inhibitory effects of pyrvinium were tested in human AML cell lines. Transcriptome analysis of Molm13 myeloid leukemia cells suggested that pyrvinium pamoate could trigger an unfolded protein response (UPR)-like pathway, including responses to extracellular stimulus [p-value = 2.78 × 10−6] and to endoplasmic reticulum stress [p-value = 8.67 × 10−7], as well as elicit metabolic reprogramming, including sulfur compound catabolic processes [p-value = 2.58 × 10−8], and responses to a redox state [p-value = 5.80 × 10−5]; on the other hand, it could elicit a pyrvinium blunted protein folding function, including protein folding [p-value = 2.10 × 10−8] and an ATP metabolic process [p-value = 3.95 × 10−4]. Subsequently, pyrvinium was verified to induce an integrated stress response (ISR), demonstrated by activation of the eIF2α-ATF4 pathway and inhibition of mTORC1 signaling, in a dose- and time-dependent manner. Additionally, pyrvinium could co-localize with mitochondria and then decrease the mitochondrial basal oxidative consumption rate, ultimately dysregulating the mitochondrial function. Similar effects were observed in cabozantinib-resistant Molm13-XR cell lines. Furthermore, pyrvinium treatment retarded Molm13 and Molm13-XR xenograft tumor growth. Thus, we concluded that pyrvinium exerts anti-tumor activity, at least, via the modulation of the mitochondrial function and by triggering ISR.
Highlights
We used the percentage of sub-G1 populations instead of the percentage of propidium iodide (PI)/Annexin V (+) populations to evaluate the extent of apoptosis, since the fluorescence background interference of pyrvinium in the PI/Annexin V signals in flow cytometry may have compromised the reliability of the results [34]
Further examination showed that pyrvinium did not inhibit other pathways known to be targeted by pyrvinium in other types of tumors, such as the signal transducer and activator of transcription 3 (STAT3) and wingless-related integration site (Wnt) pathways (Figure 1D,E); these results suggested that alternative mechanisms, including but not limited to mitochondrial mechanisms, may contribute to this robust anti-leukemic activity of pyrvinium
We revealed that pyrvinium pamoate could inhibit the fms-like tyrosine kinase 3 (FLT3) signaling pathway, and target mitochondria and induce cellular stress responses; these inhibited cell proliferation and triggered the apoptosis of Molm13 and derived
Summary
The past decades have witnessed substantial progress in the biological classification of AML [2]. Drug therapy for AML underwent significant advances in 2017 and 2018, with the US Food and Drug Administration (FDA) approving several new targeted agents [3,4]. Midostaurin [5] and gilteritinib [6] were reported to be suitable for AML patients with a fms-like tyrosine kinase 3 (FLT3) mutation. The use of these specific FLT3 inhibitors alone exhibited relatively high response rates (50–66%); the Biomedicines 2021, 9, 1869.
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