{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T02:17:27Z","timestamp":1785205047507,"version":"3.55.0"},"reference-count":62,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T00:00:00Z","timestamp":1724716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["R01 CA260749"],"award-info":[{"award-number":["R01 CA260749"]}]},{"name":"National Institutes of Health","award":["R01 CA276846"],"award-info":[{"award-number":["R01 CA276846"]}]},{"name":"National Institutes of Health","award":["P20 GM121316"],"award-info":[{"award-number":["P20 GM121316"]}]},{"name":"National Institutes of Health","award":["R00 CA208017"],"award-info":[{"award-number":["R00 CA208017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hemato"],"abstract":"<jats:p>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-\u03baB) 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-\u03baB 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.<\/jats:p>","DOI":"10.3390\/hemato5030024","type":"journal-article","created":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T11:58:46Z","timestamp":1724759926000},"page":"321-340","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Novel Anti-Cancer Agent, SpiD3, Is Cytotoxic in CLL Cells Resistant to Ibrutinib or Venetoclax"],"prefix":"10.3390","volume":"5","author":[{"given":"Alexandria P.","family":"Eiken","sequence":"first","affiliation":[{"name":"Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Schmitz","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin M.","family":"Drengler","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5096-5351","authenticated-orcid":false,"given":"Audrey L.","family":"Smith","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8933-6015","authenticated-orcid":false,"given":"Sydney A.","family":"Skupa","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kabhilan","family":"Mohan","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5802-5970","authenticated-orcid":false,"given":"Sandeep","family":"Rana","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5719-967X","authenticated-orcid":false,"given":"Sarbjit","family":"Singh","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0440-6617","authenticated-orcid":false,"given":"Jayapal Reddy","family":"Mallareddy","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6115-6373","authenticated-orcid":false,"given":"Grinu","family":"Mathew","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA"},{"name":"Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, 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