Novel Protein Disulfide Isomerase Inhibitor with Anticancer Activity in Multiple Myeloma

Vatolin, Sergei; Phillips, James G.; Jha, Babal K.; Govindgari, Shravya; Hu, Juguang; Grabowski, Dale; Parker, Yvonne; Lindner, Daniel J.; Zhong, Fei; Distelhorst, Clark W.; Smith, Mitchell R.; Cotta, Claudiu V.; Xu, Yan; Chilakala, Sujatha; Kuang, Rebecca R; Tall, Samantha; Reu, Frederic J.

doi:10.1158/0008-5472.can-15-3099

Cited by 86 publications

(89 citation statements)

References 38 publications

(40 reference statements)

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“…Many chemical compounds, such as bacitracin, arsenics or sulfhydryl reagents, have been reported to inhibit PDI by forming covalent bonds with the cysteine residues in the active sites, but they usually lack either potency or selectivity [6], [47], [48], [49]. Newly identified PDI inhibitors, such as PACMA31, and CCF642, are more selective toward PDI, but they also irreversibly bind to the active site cysteine residues and exhibit potent cytotoxicity [50], [51], [52]. This property may be of benefit for treatment of cancer effectively; however, it is apparently not suitable for treating non-malignant diseases, such as cardiovascular diseases.…”

Section: Discussionmentioning

confidence: 99%

HPW-RX40 prevents human platelet activation by attenuating cell surface protein disulfide isomerases

et al. 2017

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Protein disulfide isomerase (PDI) present at platelet surfaces has been considered to play an important role in the conformational change and activation of the integrin glycoprotein IIb/IIIa (GPIIb/IIIa) and thus enhances platelet aggregation. Growing evidences indicated that platelet surface PDI may serve as a potential target for developing of a new class of antithrombotic agents. In the present study, we investigated the effects of HPW-RX40, a chemical derivative of β-nitrostyrene, on platelet activation and PDI activity. HPW-RX40 inhibited platelet aggregation, GPIIb/IIIa activation, and P-selectin expression in human platelets. Moreover, HPW-RX40 reduced thrombus formation in human whole blood under flow conditions, and protects mice from FeCl3-induced carotid artery occlusion. HPW-RX40 inhibited the activity of recombinant PDI family proteins (PDI, ERp57, and ERp5) as well as suppressed cell surface PDI activity of platelets in a reversible manner. Exogenous addition of PDI attenuated the inhibitory effect of HPW-RX40 on GPIIb/IIIa activation. Structure-based molecular docking simulations indicated that HPW-RX40 binds to the active site of PDI by forming hydrogen bonds. In addition, HPW-RX40 neither affected the cell viability nor induced endoplasmic reticulum stress in human cancer A549 and MDA-MB-231 cells. Taken together, our results suggest that HPW-RX40 is a reversible and non-cytotoxic PDI inhibitor with antiplatelet effects, and it may have a potential for development of novel antithrombotic agents.

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Section: Discussionmentioning

confidence: 99%

HPW-RX40 prevents human platelet activation by attenuating cell surface protein disulfide isomerases

et al. 2017

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“…Moreover, a generalized inhibition of PDI activity revealed a significant sensitization of both neuroectodermal tumor cells to ER stress-mediated apoptosis induction, supporting the crucial role played by these enzymes under ER stress conditions (20, 66). Importantly, although the exact role(s) played by PDI in cancer progression is still not well established, PDI inhibition appears as a fascinating novel strategy for sensitizing different cancer types beyond neuroectodermal malignancies to apoptosis, such as multiple myeloma and HCC (67, 68). However, is also important to note that despite the intense study in last decades, there are still no selective PDI inhibitors for clinical use.…”

Section: Targeting Er Stress As a Therapeutic Strategymentioning

confidence: 99%

Endoplasmic Reticulum Stress, Unfolded Protein Response, and Cancer Cell Fate

et al. 2017

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Perturbation of endoplasmic reticulum (ER) homeostasis results in a stress condition termed “ER stress” determining the activation of a finely regulated program defined as unfolded protein response (UPR) and whose primary aim is to restore this organelle’s physiological activity. Several physiological and pathological stimuli deregulate normal ER activity causing UPR activation, such as hypoxia, glucose shortage, genome instability, and cytotoxic compounds administration. Some of these stimuli are frequently observed during uncontrolled proliferation of transformed cells, resulting in tumor core formation and stage progression. Therefore, it is not surprising that ER stress is usually induced during solid tumor development and stage progression, becoming an hallmark of such malignancies. Several UPR components are in fact deregulated in different tumor types, and accumulating data indicate their active involvement in tumor development/progression. However, although the UPR program is primarily a pro-survival process, sustained and/or prolonged stress may result in cell death induction. Therefore, understanding the mechanism(s) regulating the cell survival/death decision under ER stress condition may be crucial in order to specifically target tumor cells and possibly circumvent or overcome tumor resistance to therapies. In this review, we discuss the role played by the UPR program in tumor initiation, progression and resistance to therapy, highlighting the recent advances that have improved our understanding of the molecular mechanisms that regulate the survival/death switch.

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“…Leveraging the UPR-mediated cell death pathway led to the development of a new class of therapeutics that target protein disulfide isomerase (PDI), a redox-dependent protein folding enzyme with isomerase and chaperone activity. In multiple myeloma cells, inhibition of PDI led to an accumulation of unfolded/misfolded proteins demonstrated by increased ubiquitination, rapid cell death through activation of the UPR, and enhanced efficacy of FDA-approved proteasome inhibitors [7,8]. PDI is an emerging drug target in oncology, and, while the anti-tumor effects of PDI inhibition have been well documented, the consequence of PDI modulation on healthy immune cells has not been assessed.…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic Reticulum Protein Disulfide Isomerase Shapes T Cell Efficacy for Adoptive Cellular Therapy of Tumors

Hurst

Lawrence

Angeles

et al. 2019

Cells

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Effective cancer therapies simultaneously restrict tumor cell growth and improve anti-tumor immune responses. Targeting redox-dependent protein folding enzymes within the endoplasmic reticulum (ER) is an alternative approach to activation of the unfolded protein response (UPR) and a novel therapeutic platform to induce malignant cell death. E64FC26 is a recently identified protein disulfide isomerase (PDI) inhibitor that activates the UPR, oxidative stress, and apoptosis in tumor cells, but not normal cell types. Given that targeting cellular redox homeostasis is a strategy to augment T cell tumor control, we tested the effect of E64FC26 on healthy and oncogenic T cells. In stark contrast to the pro-UPR and pro-death effects we observed in malignant T cells, we found that E64FC26 improved viability and limited the UPR in healthy T cells. E64FC26 treatment also diminished oxidative stress and decreased global PDI expression in normal T cells. Oxidative stress and cell death are limited in memory T cells and we found that PDI inhibition promoted memory traits and reshaped T cell metabolism. Using adoptive transfer of tumor antigen-specific CD8 T cells, we demonstrate that T cells activated and expanded in the presence of E64FC26 control tumor growth better than vehicle-matched controls. Our data indicate that PDI inhibitors are a new class of drug that may dually inhibit tumor cell growth and improve T cell tumor control.

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Novel Protein Disulfide Isomerase Inhibitor with Anticancer Activity in Multiple Myeloma

Cited by 86 publications

References 38 publications

HPW-RX40 prevents human platelet activation by attenuating cell surface protein disulfide isomerases

HPW-RX40 prevents human platelet activation by attenuating cell surface protein disulfide isomerases

Endoplasmic Reticulum Stress, Unfolded Protein Response, and Cancer Cell Fate

Endoplasmic Reticulum Protein Disulfide Isomerase Shapes T Cell Efficacy for Adoptive Cellular Therapy of Tumors

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