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Article

The Novel Anti-Cancer Agent, SpiD3, Is Cytotoxic in CLL Cells Resistant to Ibrutinib or Venetoclax

by
Alexandria P. Eiken
1,
Elizabeth Schmitz
1,
Erin M. Drengler
1,
Audrey L. Smith
1,
Sydney A. Skupa
1,
Kabhilan Mohan
1,
Sandeep Rana
1,
Sarbjit Singh
1,
Jayapal Reddy Mallareddy
1,
Grinu Mathew
1,2,
Amarnath Natarajan
1,2 and
Dalia El-Gamal
1,2,*
1
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
2
Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
*
Author to whom correspondence should be addressed.
Hemato 2024, 5(3), 321-339; https://doi.org/10.3390/hemato5030024
Submission received: 3 July 2024 / Revised: 9 August 2024 / Accepted: 23 August 2024 / Published: 27 August 2024
(This article belongs to the Section Leukemias)
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Abstract

Background: B-cell receptor (BCR) signaling is a central driver in chronic lymphocytic leukemia (CLL), along with the activation of pro-survival pathways (e.g., NF-κB) and aberrant anti-apoptotic mechanisms (e.g., BCL2) culminating to CLL cell survival and drug resistance. Front-line targeted therapies such as ibrutinib (BTK inhibitor) and venetoclax (BCL2 inhibitor) have radically improved CLL management. Yet, persisting CLL cells lead to relapse in ~20% of patients, signifying the unmet need of inhibitor-resistant refractory CLL. SpiD3 is a novel spirocyclic dimer of analog 19 that displays NF-κB inhibitory activity and preclinical anti-cancer properties. Recently, we have shown that SpiD3 inhibits CLL cell proliferation and induces cytotoxicity by promoting futile activation of the unfolded protein response (UPR) pathway and generation of reactive oxygen species (ROS), resulting in the inhibition of protein synthesis in CLL cells. Methods: We performed RNA-sequencing using CLL cells rendered resistant to ibrutinib and venetoclax to explore potential vulnerabilities in inhibitor-resistant and SpiD3-treated CLL cells. Results: The transcriptomic analysis of ibrutinib- or venetoclax-resistant CLL cell lines revealed ferroptosis, UPR signaling, and oxidative stress to be among the top pathways modulated by SpiD3 treatment. By examining SpiD3-induced protein aggregation, ROS production, and ferroptosis in inhibitor-resistant CLL cells, our findings demonstrate cytotoxicity following SpiD3 treatment in cell lines resistant to current front-line CLL therapeutics. Conclusions: Our results substantiate the development of SpiD3 as a novel therapeutic agent for relapsed/refractory CLL disease.
Keywords: chronic lymphocytic leukemia (CLL); drug resistance; SpiD3; ibrutinib; venetoclax; unfolded protein response (UPR); ferroptosis; oxidative stress chronic lymphocytic leukemia (CLL); drug resistance; SpiD3; ibrutinib; venetoclax; unfolded protein response (UPR); ferroptosis; oxidative stress

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MDPI and ACS Style

Eiken, A.P.; Schmitz, E.; Drengler, E.M.; Smith, A.L.; Skupa, S.A.; Mohan, K.; Rana, S.; Singh, S.; Mallareddy, J.R.; Mathew, G.; et al. The Novel Anti-Cancer Agent, SpiD3, Is Cytotoxic in CLL Cells Resistant to Ibrutinib or Venetoclax. Hemato 2024, 5, 321-339. https://doi.org/10.3390/hemato5030024

AMA Style

Eiken AP, Schmitz E, Drengler EM, Smith AL, Skupa SA, Mohan K, Rana S, Singh S, Mallareddy JR, Mathew G, et al. The Novel Anti-Cancer Agent, SpiD3, Is Cytotoxic in CLL Cells Resistant to Ibrutinib or Venetoclax. Hemato. 2024; 5(3):321-339. https://doi.org/10.3390/hemato5030024

Chicago/Turabian Style

Eiken, Alexandria P., Elizabeth Schmitz, Erin M. Drengler, Audrey L. Smith, Sydney A. Skupa, Kabhilan Mohan, Sandeep Rana, Sarbjit Singh, Jayapal Reddy Mallareddy, Grinu Mathew, and et al. 2024. "The Novel Anti-Cancer Agent, SpiD3, Is Cytotoxic in CLL Cells Resistant to Ibrutinib or Venetoclax" Hemato 5, no. 3: 321-339. https://doi.org/10.3390/hemato5030024

APA Style

Eiken, A. P., Schmitz, E., Drengler, E. M., Smith, A. L., Skupa, S. A., Mohan, K., Rana, S., Singh, S., Mallareddy, J. R., Mathew, G., Natarajan, A., & El-Gamal, D. (2024). The Novel Anti-Cancer Agent, SpiD3, Is Cytotoxic in CLL Cells Resistant to Ibrutinib or Venetoclax. Hemato, 5(3), 321-339. https://doi.org/10.3390/hemato5030024

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