{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T03:03:59Z","timestamp":1788318239415,"version":"build-2803163510"},"reference-count":47,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,6,15]],"date-time":"2024-06-15T00:00:00Z","timestamp":1718409600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Marshall Eliuk Fund","award":["RES0054787"],"award-info":[{"award-number":["RES0054787"]}]},{"name":"Marshall Eliuk Fund","award":["RES005614"],"award-info":[{"award-number":["RES005614"]}]},{"name":"Kipnes Foundation","award":["RES0054787"],"award-info":[{"award-number":["RES0054787"]}]},{"name":"Kipnes Foundation","award":["RES005614"],"award-info":[{"award-number":["RES005614"]}]},{"name":"University Hospital Foundations","award":["RES0054787"],"award-info":[{"award-number":["RES0054787"]}]},{"name":"University Hospital Foundations","award":["RES005614"],"award-info":[{"award-number":["RES005614"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Venetoclax and obinutuzumab are becoming frontline therapies for chronic lymphocytic leukemia (CLL) patients. Unfortunately, drug resistance still occurs, and the combination could be immunosuppressive. Lysosomes have previously been identified as a target for obinutuzumab cytotoxicity in CLL cells, but the mechanism remains unclear. In addition, studies have shown that lysosomotropic agents can cause synergistic cell death in vitro when combined with the BTK inhibitor, ibrutinib, in primary CLL cells. This indicates that targeting lysosomes could be a treatment strategy for CLL. In this study, we have shown that obinutuzumab induces lysosome membrane permeabilization (LMP) and cathepsin D release in CLL cells. Inhibition of cathepsins reduced obinutuzumab-induced cell death in CLL cells. We further determined that the lysosomotropic agent siramesine in combination with venetoclax increased cell death in primary CLL cells through an increase in reactive oxygen species (ROS) and cathepsin release. Siramesine treatment also induced synergistic cytotoxicity when combined with venetoclax. Microenvironmental factors IL4 and CD40L or incubation with HS-5 stromal cells failed to significantly protect CLL cells from siramesine- and venetoclax-induced apoptosis. We also found that siramesine treatment inhibited autophagy through reduced autolysosomes. Finally, the autophagy inhibitor chloroquine failed to further increase siramesine-induced cell death. Taken together, lysosome-targeting drugs could be an effective strategy in combination with venetoclax to overcome drug resistance in CLL.<\/jats:p>","DOI":"10.3390\/cells13121041","type":"journal-article","created":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T04:48:12Z","timestamp":1718599692000},"page":"1041","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Lysosome-Disrupting Agents in Combination with Venetoclax Increase Apoptotic Response in Primary Chronic Lymphocytic Leukemia (CLL) Cells Mediated by Lysosomal Cathepsin D Release and Inhibition of Autophagy"],"prefix":"10.3390","volume":"13","author":[{"given":"Madhumita S.","family":"Manivannan","sequence":"first","affiliation":[{"name":"Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nirav","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2570-339X","authenticated-orcid":false,"given":"Anthea","family":"Peters","sequence":"additional","affiliation":[{"name":"Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada"},{"name":"Cross Cancer Institute, Alberta Health Services, Edmonton, AB T5J 3E4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6614-083X","authenticated-orcid":false,"given":"James B.","family":"Johnston","sequence":"additional","affiliation":[{"name":"CancerCare Manitoba Research Institute, Hematologist\/Oncologist, CancerCare Manitoba, Winnipeg, MB R3E 0V9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spencer B.","family":"Gibson","sequence":"additional","affiliation":[{"name":"Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada"},{"name":"Department of Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada"},{"name":"Department of Biochemistry and Medical Genetics, Faculty of Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1182\/asheducation-2002.1.193","article-title":"Chronic Lymphocytic Leukemia","volume":"1","author":"Kay","year":"2002","journal-title":"Hematology (Am Soc Hematol Educ Program)"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Bewarder, M., Stilgenbauer, S., Thurner, L., and Kaddu-Mulindwa, D. 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