Asbestos and Inactive Mesothelioma Cells

Asbestos and Inactive Mesothelioma Cells

One interesting study is called, “c-Jun N-terminal Kinase Contributes to Apoptotic Synergy Induced by Tumor Necrosis Factor-related Apoptosis-inducing Ligand plus DNA Damage in Chemoresistant, p53 Inactive Mesothelioma Cells” by Claire Vivo, Weihong Liu and V. Courtney Broaddus – July 11, 2003 The Journal of Biological Chemistry, 278, 25461-25467.  Here is an excerpt: “Abstract – Apoptotic resistance of cancer cells may be overcome by the combination of treatments that activate the two major apoptotic pathways: (i) the death receptor pathway activated by death ligands and (ii) the DNA damage pathway activated by chemotherapy. We have previously shown that mesothelioma cells, resistant to most treatments, are sensitive to the combination of the death ligand tumor necrosis factor-related apoptosis inducing ligand (TRAIL/Apo2L) plus chemotherapy. We investigated a possible role for c-Jun N-terminal kinase (JNK) in the synergistic effect, knowing that JNK can be activated separately by TRAIL and by DNA damage. We chose to study the M28 and REN human mesothelioma cell lines, which are p53-inactivated, to avoid an interaction between p53 and JNK. We showed that JNK was activated by TRAIL and by etoposide and that the activation was enhanced by the combination of the two treatments. We found this activation to be caspase-independent. To inhibit the JNK pathway, we used either dominant-negative constructs of JNK1 and JNK2 (compared with dominant-negative caspase 9) or a chemical inhibitor of the JNK pathway (SP600125). In cells treated with TRAIL plus etoposide, JNK inhibition increased cell survival and decreased apoptosis significantly. In transfected M28 cells, the effect of JNK inhibition was as great as that of the dominant-negative caspase 9 construct. We conclude that JNK contributes to the synergistic effect of TRAIL combined with DNA damage by mediating signals independent of p53 leading to apoptosis.

Previous SectionNext SectionDefects in normal apoptotic programs contribute to the formation of tumors (1) and interfere with the tumor response to conventional therapy (2, 3). Abnormal apoptotic responses may arise from defective apoptotic machinery, as by mutation in p53 or up-regulation of anti-apoptotic Bcl-2 (B-cell lymphoma-2), which provide both a survival advantage and resistance to therapy (4). Among strategies to bypass sites of apoptotic resistance are the use of death receptor ligands that can directly engage the apoptotic caspases of the cell. Indeed, one death receptor ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L),1 appears to have selective activity toward transformed or malignant cells (,5). In some cases, the action of TRAIL and other death ligands can be enhanced significantly by concomitant DNA damage resulting in a synergistic apoptotic response. Although this synergistic apoptosis has been described in many tumor cells (6), the mechanism is not yet understood. Understanding the mechanism of synergy between two different apoptotic stimuli that effectively bypass sites of apoptotic resistance may provide insights into more effective anti-tumor approaches.”

Another interesting study is called, “Peritoneal cystic mesothelioma: A case series” –
Piensero Scientifico, Roma, ITALIE  (1911) (Revue) 2003, vol. 89, no1, pp. 31-35.  Here is an excerpt: “Abstract – Background: Cystic peritoneal mesothelioma is a rare disease associated with a favorable short-term prognosis. Longer follow-up documenting a persistence of symptoms and a high rate of recurrence after debulking surgery along with an uncertain natural history prompt a re-valuation of prior treatment recommendations. No prior long-term clinical study of these patients is available. Methods: The experience with five cases of cystic peritoneal mesothelioma, four females and one male, are reviewed. All of these patients were treated with cytoreductive surgery with peritonectomy procedures and heated Intraoperative intraperitoneal chemotherapy. CT, pathology and current status were investigated in order to learn more about the natural history of this disease. Results: All patients were symptomatic from abdominal distention and three of the four complained of severe pain. Female patients complained of long periods of recurrent abdominal and pelvic pain poorly managed by oral analgesics. In one patient prolonged conservative management over ten years resulted in transition to an invasive process with extensive lymph nodal metastases. Her prognosis for long-term survival Is guarded because of mesothelioma extension Into the chest. Disease control of both ascltes and pain In the abdomen and pelvis was achieved In all five patients treated with cytoreductive surgery plus intraperitoneal chemotherapy. Conclusions: Cystic peritoneal mesothelioma should no longer be referred to as “benign” cystic mesothelloma. An aggressive approach with complete disease eradication is the correct goal of treatment. From our experience, cytoreductive surgery to remove all visible tumor and intraperitoneal chemotherapy to control microscopic residual disease will help patients with peritoneal cystic mesothelioma to remain symptom- and disease-free over an extended time period with a single surgical intervention. Disease eradication may prevent the transition to an aggressive and fatal disease process.”

Monty Wrobleski is the author of this article.  For more information please click on the following links

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