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Dr. Halaby is a Professor of Biology and a Cancer Scientist. Breast cancer is the deadliest malignancy in women globally. However it also kills men, the transgendered, and people from all racial and ethnic backgrounds. Dr. Halaby's research focuses on investigating lysosomal-mediated apoptosis (LMA) in human breast cancer cells exposed to triptolide (Thunder God Vine). This Chinese herb has been used in Traditional Chinese Medicine (TCM) for centuries to treat anti-inflammatory and autoimmune disorders. Dr. Halaby and his team showed that triptolide concentrations, which are 1,000X less than chemotherapeutic drugs, induce cell death in treatment-resistant breast cancer cell lines. This is significant because it suggests that LMA may serve as an effective therapy for tumors that become drug-resistant.
Although chemotherapeutic drugs are toxic to human cells, they are still the primary treatment modality for various malignancies. However, resistance to chemotherapeutic drugs is a major obstacle to curative cancer treatment. Lysosomes, the favorite organelle of the Halaby Lab, participate in cellular digestion. Our lab has demonstrated that lysosomes play dual, and opposing, roles in tumorigenesis. Lysosomal enzymes can promote angiogenesis and metastasis on one hand. On the other hand, lysosomal proteases can induce senescence and apoptosis. Dr. Halaby's research utilizes cellular and molecular strategies that specifically and intentionally target lysosomes to kill cancer cells.
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Induction of lysosomal-mediated apoptosis in chemoresistant human breast and prostate cancer cells using triptolide (Thunder God Vine), a Chinese herb that has been used in traditional Chinese medicine for over two centuries. We have demonstrated that triptolide's apoptotic abilities are due, in part, to it being a lysosomotropic agent.
- 9:00 am - 10:30 am
- 8:30 am - 10:00 am
- Lysosomes contribute to multidrug resistance in cancer cells
- Sabbatical Research using CRISPR to Knock Out FOXO3 Gene in Cancer Cells at the University of Texas Rio Grande Valley
- Immunosuppressive, Anti-inflammatory, and Anticancer Properties of Triptolide
- Role of Lysosomes in Cancer Therapy
- Triptolide: Novel Anticancer Agent for Chemoresistant Cancer Cells that are Caspase-3 Deficient
- Triptolide Induces Lysosomal-Mediated Programmed Cell Death in MCF-7 Breast Cancer Cells
- Apoptosis and Autoimmune Disorders Book Chapter
- Apoptosis and Photoreceptors
Cancer cells become resistant to treatment protocols by mutating their DNA sequence: inactivating pro-apoptotic and tumor suppressor genes; activating oncogenes; etc. Furthermore, most chemotherapy drugs are nonspecific, killing all rapidly dividing cells including healthy ones. Cancer cells possess larger and more active lysosomes compared to normal cells. Therefore, targeting lysosomes may lead to the design of novel, more effective anticancer drugs.
Lysosomes contain approximately 50 degradative enzymes that have the capability of digesting all of the molecules of a cell. Our results demonstrate that triptolide modulates lysosomal membrane permeability in such a way that it results in the release of the lysosomal enzymes, such as cathepsin B, into the cytosol. Furthermore, we show that triptolide induces lysosomal-mediated cell death in MCF-7 breast and DU-145 prostate cancer cells. This work is significant because MCF-7 cells lack caspase-3, a key executioner protein in the intrinsic and extrinsic apoptotic pathways. We and others have shown that tumors that contain mutant or deficient caspase-3 become treatment-resistant. Therefore, lysosomal-mediated cell death provides an important alternative mechanism for eliminating apoptosis-resistant tumors.
MCF-7 cells lack the caspase-3 protein due to a mutation. This protein plays a key role as one of the executioner caspases in the apoptotic pathways. Furthermore, it has been shown by others that cancer cells that are deficient for caspase-3 acquire resistance to chemotherapy and/or radiation. Therefore, our hypothesis is that lysosomal-mediated programmed cell death, which we have demonstrated is independent of caspase-3, may be utilized to treat apoptosis-resistant cancer cells.
We have demonstrated that triptolide exerts its anticancer effects via a lysosomal-mediated mechanism. The significance of these findings is that triptolide may serve as a novel natural anticancer agent that is effective against apoptosis-resistant (chemotherapy-resistant and radiation-resistant)tumors.
We provide evidence suggesting that triptolide disrupts the lysosomal membrane, which results in the leakage of lysosomal enzymes to the cytosol where the enzymes trigger the intrinsic apoptotic pathway.