The Anticancer Agent Di-2-pyridylketone 4,4-Dimethyl-3-thiosemicarbazone (Dp44mT) Overcomes Prosurvival Autophagy by Two Mechanisms

Abstract

Background: Autophagy is a prosurvival mechanism contributing to resistance against anticancer agents. Results: We demonstrate that the selective antitumor thiosemicarbazone di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) increases autophagosome synthesis but induces cell death by reducing autophagosome degradation. Conclusion: Dp44mT overcomes autophagy and utilizes the autophagic machinery to provoke cell death. Significance: These results indicate a new mechanism by which Dp44mT induces tumor cell death.

Novel Thiosemicarbazones Regulate the Signal Transducer and Activator of Transcription 3 (STAT3) Pathway: Inhibition of Constitutive and Interleukin 6–Induced Activation by Iron Depletion

“…2004; Kovacevic et al, 2011;Kovacevic et al, 2013), leading to inhibition of the epithelial-mesenchymal transition (Chen et al, 2012); 4) lysosomal membrane permeabilization mediated by the generation of redox active copper complexes (Yuan et al, 2004;Richardson et al, 2006;Lovejoy et al, 2011), resulting in impaired autophagy (Gutierrez et al, 2014) and the induction of apoptosis (Gutierrez et al, 2014;Sahni et al, 2014); 5) inhibition of multiple oncogenic cellular signaling pathways such as phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and transforming growth factor-b (TGF-b) pathways and upregulation of tumor-suppressive phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and SMAD4 (Dixon et al, 2013;Kovacevic et al, 2013); 6) inhibition of cyclin D1 expression (Kulp et al, 1996;Gao and Richardson, 2001;NurtjahjaTjendraputra et al, 2007); and 7) inhibition of the rate-limiting step of DNA synthesis catalyzed by the iron-containing enzyme ribonucleotide reductase . The relative contribution of each of these targets to the inhibition of tumor cell growth is yet to be deciphered, but may depend on the type and stage of the neoplasm.…”

Lysosomal membrane stability plays a major role in the cytotoxic activity of the anti-proliferative agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT)

“…These agents demonstrate marked and selective anti-tumor and anti-metastatic activity against a range of belligerent tumors in vitro and in vivo [5,[15][16][17][18][19][20][21][22][23]25]. Moreover, the ability of these ligands to induce LMP [6,7] is integrally linked to their activity in terms of overcoming: (1) pro-survival autophagy (Fig. 1Bi) by increasing autophagosome biogenesis and preventing autolysosomal formation by disrupting lysosomes (Fig.…”

“…1A; [5,[15][16][17][18][19][20][21][22][23][24][25]), was shown to be lysosomotropic and trapped within lysosomes due to the acidic pH of these vesicles [6]. Within these organelles, Dp44mT forms cytotoxic copper complexes that generate reactive oxygen species (ROS), resulting in lysosomal membrane permeabilization (LMP) that induces tumor cell death [5][6][7].…”

“…It can also potentially provide a strategy for the treatment of apoptosis-and multidrug-resistant cancers [3][4][5]. Evidence supporting the role of lysosomes as cell death mediators is demonstrated from studies of compounds that directly target lysosomes to affect the integrity of their membranes [5][6][7][8][9][10][11][12][13][14].…”

“…1Bi) by increasing autophagosome biogenesis and preventing autolysosomal formation by disrupting lysosomes (Fig. 1Bii; [6,7]); and (2) multi-drug resistance [5]. Hence, the detailed molecular mechanism of action of Dp44mT in terms of inducing LMP is vital to understand.…”