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The lysosomotropic agent siramesine induces cell death in prostate cancer cells and synergizes with the tyrosine kinase inhibitor lapatinib
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- Author / Creator
- Bhatti, Ilsa
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Prostate cancer is the most diagnosed cancer affecting Canadian men. Prostate tumors that progress from localized disease to advanced stages show resistance to standard therapy, a major problem that requires alternative treatments. One new treatment possibility is targeting lysosomal membrane disruption with lysosomotropic agents, leading to lysosome membrane permeabilization (LMP) and triggering pathways that result in cell death. Lysosomotropic agents can also be combined with other targeted agents to increase the efficacy of cell death induction in different types of cancer. Previous research has shown that the most effective lysosomotropic agent for inducing ROS generation, lysosome membrane permeabilization, and cell death in prostate cancer cell lines is siramesine which inhibits acidic sphingomyelinase. My results indicate that combining siramesine with lapatinib, a tyrosine kinase inhibitor for EGFR and HER2, synergistically increased prostate cancer cell death. This combination induced cell death to a greater extent in an aggressive castration-resistant prostate cell line compared to an androgen-sensitive prostate cancer cell line or non-malignant cell line. The synergistic increase in cell death with the combination treatment is mediated by increased ROS levels following lysosome membrane permeabilization but is independent of the actions of Cathepsin D released after LMP and caspase activation. The combination also failed to result in BID cleavage. Combining siramesine and lapatinib resulted in decreased expression of MCL-1, a BCL-2 family member, and increased cellular and mitochondrial ROS. Treating cells with the antioxidant alpha-tocopherol attenuated the cell death resulting from siramesine alone or the combination treatment, suggesting a role for ROS in the caspase-independent cell death. In other cancer cells, siramesine induces autophagy (self-eating). I found that siramesine and lapatinib caused accumulation of the autophagic markers LC3-II and p62 and combining the combination treatment with chloroquine administration did not further increase expression indicating that siramesine and lapatinib fail to increase autophagic flux. This suggests the combination treatment inhibits autophagy and damage to the lysosome through siramesine prevents the progression of the autophagic pathway and subsequent degradation of the autophagic markers. These results indicate that combination treatments between lysosomotropic agents such as siramesine and targeted inhibitors such as the tyrosine kinase inhibitor lapatinib induce ROS driven cell death in prostate cancer cell lines, but that further work is needed to determine approved treatment options to target these pathways and provide an alternative treatment strategy in the management of drug resistant aggressive prostate cancers.
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- Graduation date
- Fall 2024
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- Type of Item
- Thesis
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- Degree
- Master of Science
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- License
- This thesis is made available by the University of Alberta Library with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.