Abstract
Malignant pleural mesothelioma (MPM) is an asbestos-related thoracic malignancy that is characterized by late metastases, and resistance to therapeutic modalities. The toxic side-effects of MPM therapies often limit their clinical effectiveness, thus necessitating development of new agents to effectively treat and manage this disease in clinic. CARP-1 functional mimetics (CFMs) are a novel class of compounds that inhibit growth of diverse cancer cell types. Here we investigated MPM cell growth suppression by the CFMs and the molecular mechanisms involved. CFM-1, -4, and -5 inhibited MPM cell growth, in vitro, in part by stimulating apoptosis. Apoptosis by CFM-4 involved activation of pro-apoptotic stress-activated protein kinases (SAPKs) p38 and JNK, elevated CARP-1 expression, cleavage of PARP1, and loss of the oncogene c-myc as well as mitotic cyclin B1. Treatments of MPM cells with CFM-4 resulted in depletion of NF-κB signaling inhibitor ABIN1 and Inhibitory κB (IκB)α and β, while increasing expression of pro-apoptotic death receptor (DR) 4 protein. CFM-4 enhanced expression of serine-phosphorylated podoplanin and cleavage of vimetin. CFMs also attenuated biological properties of the MPM cells by blocking their abilities to migrate, form colonies in suspension, and invade through the matrix-coated membranes. Both podoplanin and vimentin regulate processes of cell motility and invasion, and their expression often correlates with metastatic disease, and poor prognosis. The fact that phosphorylation of serines in the cytoplasmic domain of podoplanin interferes with processes of cellular motility, CFM-4-dependent elevated phosphorylated podoplanin and cleavage of vimentin underscore a metastasis inhibitory property of these compounds, and suggest that CFMs and/or their future analogs have potential as anti-MPM agents.
Highlights
Malignant pleural mesothelioma (MPM) is a lethal asbestosrelated malignancy [1]
Since Cisplatin is often used as a frontline therapy for MPM in clinic, here we utilized H2461 and H2373 MPM cells [16] in a proof-of-concept study to further investigate anti-MPM efficacies of CARP-1 functional mimetics (CFMs), and to determine whether CFMs are superior to Cisplatin in inhibiting MPM cell growth
We investigated whether CFMs promoted apoptosis to inhibit MPM cell growth
Summary
Malignant pleural mesothelioma (MPM) is a lethal asbestosrelated malignancy [1]. Scores of workers have been exposed to asbestos throughout world. Since asbestos exposure has been identified as a risk factor in diseases including asbestosis, lung cancer and MPM [1], it is estimated that approximately 2,000– 3,000 people will be diagnosed as MPM patients each year in the US. The use of asbestos has been significantly curtailed, the incidence of asbestos-related diseases including MPM is expected to continue in the decade in the United States and Europe [3,4]. The multimodality treatment for MPM in the clinic often consists of surgery, adjuvant or neoadjuvant chemotherapy, and radiation [2]. The median survival of MPM patients ranges from 9–17 months, and remains unacceptably low [3]. Development of novel treatment strategies for MPM is warranted to improve the survival outcome in patients and overcome resistance to currently available chemotherapies
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