scholarly journals A novel BH3-mimetic, AZD0466, targeting BCL-XL and BCL-2 is effective in pre-clinical models of malignant pleural mesothelioma

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Surein Arulananda ◽  
Megan O’Brien ◽  
Marco Evangelista ◽  
Laura J. Jenkins ◽  
Ashleigh R. Poh ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Malignant Pleural Mesothelioma ◽  
Standard Of Care ◽  
Clinical Findings ◽  
Pleural Mesothelioma ◽  
Apoptosis Pathway ◽  
High Level ◽  
Bh3 Mimetic

AbstractMalignant pleural mesothelioma (MPM) is an aggressive cancer with treatment limited to Cisplatin and Pemetrexed chemotherapy. Recently, we showed that drugs targeting the BCL-2-regulated apoptosis pathway could kill MPM cell lines in vitro, and control tumor growth in vivo. These studies showed BCL-XL was the dominant pro-survival BCL-2 family member correlating with its high-level expression in cells and patient tumor samples. In this study we show another inhibitor, AZD4320 that targets BCL-XL (and BCL-2), can also potently kill MPM tumor cells in vitro (EC50 values in the 200 nM range) and this effect is enhanced by co-inhibition of MCL-1 using AZD5991. Moreover, we show that a novel nanoparticle, AZD0466, where AZD4320 is chemically conjugated to a PEGylated poly-lysine dendrimer, was as effective as standard-of-care chemotherapy, Cisplatin, at inhibiting tumor growth in mouse xenograft studies, and this effect was enhanced when both drugs were combined. Critically, the degree of thrombocytopenia, an on-target toxicity associated with BCL-XL inhibition, was significantly reduced throughout the treatment period compared to other BCL-XL-targeting BH3-mimetics. These pre-clinical findings provide a rationale for the future clinical evaluation for novel BH3-mimetic formulations in MPM, and indeed, other solid tumor types dependent on BCL-XL.

scholarly journals Blocking the GITR-GITRL pathway to overcome resistance to therapy in sarcomatoid malignant pleural mesothelioma

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Meilin Chan ◽  
Licun Wu ◽  
Zhihong Yun ◽  
Trevor D. McKee ◽  
Michael Cabanero ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Malignant Pleural Mesothelioma ◽  
Neutralizing Antibodies ◽  
Pleural Mesothelioma ◽  
Spheroid Formation ◽  
Resistance To Therapy ◽  
Sarcomatoid Mesothelioma

AbstractMalignant pleural mesothelioma (MPM) is an aggressive neoplasm originating from the pleura. Non-epithelioid (biphasic and sarcomatoid) MPM are particularly resistant to therapy. We investigated the role of the GITR-GITRL pathway in mediating the resistance to therapy. We found that GITR and GITRL expressions were higher in the sarcomatoid cell line (CRL5946) than in non-sarcomatoid cell lines (CRL5915 and CRL5820), and that cisplatin and Cs-137 irradiation increased GITR and GITRL expressions on tumor cells. Transcriptome analysis demonstrated that the GITR-GITRL pathway was promoting tumor growth and inhibiting cell apoptosis. Furthermore, GITR+ and GITRL+ cells demonstrated increased spheroid formation in vitro and in vivo. Using patient derived xenografts (PDXs), we demonstrated that anti-GITR neutralizing antibodies attenuated tumor growth in sarcomatoid PDX mice. Tumor immunostaining demonstrated higher levels of GITR and GITRL expressions in non-epithelioid compared to epithelioid tumors. Among 73 patients uniformly treated with accelerated radiation therapy followed by surgery, the intensity of GITR expression after radiation negatively correlated with survival in non-epithelioid MPM patients. In conclusion, the GITR-GITRL pathway is an important mechanism of autocrine proliferation in sarcomatoid mesothelioma, associated with tumor stemness and resistance to therapy. Blocking the GITR-GITRL pathway could be a new therapeutic target for non-epithelioid mesothelioma.

scholarly journals Temsirolimus Inhibits Malignant Pleural Mesothelioma Growth In Vitro and In Vivo: Synergism with Chemotherapy

2011 ◽  
Vol 6 (5) ◽  
pp. 852-863 ◽  
Author(s):  
Mir Alireza Hoda ◽  
Amir Mohamed ◽  
Bahil Ghanim ◽  
Martin Filipits ◽  
Balazs Hegedus ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Pleural Mesothelioma

scholarly journals Reduction of estradiol in human malignant pleural mesothelioma tissues may prevent tumour growth, as implied by in in-vivo and in-vitro models

Oncotarget ◽  
2016 ◽  
Vol 7 (30) ◽  
pp. 47116-47126 ◽  
Author(s):  
Barbara Nuvoli ◽  
Andrea Sacconi ◽  
Giancarlo Cortese ◽  
Sabrina Germoni ◽  
Bruno Murer ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Tumour Growth ◽  
In Vitro Models ◽  
Pleural Mesothelioma

scholarly journals Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of human malignant pleural mesothelioma

2019 ◽  
Vol 116 (6) ◽  
pp. 2226-2231 ◽  
Author(s):  
Tania Villanova ◽  
Iacopo Gesmundo ◽  
Valentina Audrito ◽  
Nicoletta Vitale ◽  
Francesca Silvagno ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Cell Lines ◽  
Malignant Pleural Mesothelioma ◽  
Pleural Mesothelioma ◽  
Growth Hormone Releasing Hormone ◽  
Releasing Hormone ◽  
Ghrh Antagonists

Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated with exposure to asbestos, with poor prognosis and no effective therapies. The strong inhibitory activities of growth hormone-releasing hormone (GHRH) antagonists have been demonstrated in different experimental human cancers, including lung cancer; however, their role in MPM remains unknown. We assessed the effects of the GHRH antagonists MIA-602 and MIA-690 in vitro in MPM cell lines and in primary MPM cells, and in vivo in MPM xenografts. GHRH, GHRH receptor, and its main splice variant SV1 were found in all the MPM cell types examined. In vitro, MIA-602 and MIA-690 reduced survival and proliferation in both MPM cell lines and primary cells and showed synergistic inhibitory activity with the chemotherapy drug pemetrexed. In MPM cells, GHRH antagonists also regulated activity and expression of apoptotic molecules, inhibited cell migration, and reduced the expression of matrix metalloproteinases. These effects were accompanied by impairment of mitochondrial activity and increased production of reactive oxygen species. In vivo, s.c. administration of MIA-602 and MIA-690 at the dose of 5 μg/d for 4 wk strongly inhibited the growth of MPM xenografts in mice, along with reduction of tumor insulin-like growth factor-I and vascular endothelial growth factor. Overall, these results suggest that treatment with GHRH antagonists, alone or in association with chemotherapy, may offer an approach for the treatment of MPM.

Combination therapy of zibotentan with cisplatinum and paclitaxel is an effective regimen for epithelial ovarian cancerThis article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research.

2010 ◽  
Vol 88 (6) ◽  
pp. 676-681 ◽  
Author(s):  
Laura Rosanò ◽  
Roberta Cianfrocca ◽  
Francesca Spinella ◽  
Valeriana Di Castro ◽  
Pier Giorgio Natali ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Combination Therapy ◽  
Tumor Growth ◽  
Standard Of Care ◽  
Tumor Grade ◽  
Proliferation Index ◽  
Clinical Trial Results

In human ovarian carcinoma, the endothelin-1 (ET-1) / endothelin A receptor (ETAR) axis is overexpressed, correlating with tumor grade. Moreover, ETAR activation by ET-1 affects cell proliferation, survival, angiogenesis, and invasion. ETAR blockade with zibotentan (ZD4054), a specific ETAR antagonist, significantly inhibits ovarian cancer growth in vitro and in vivo, underscoring the relevance of this pathway as a target for cancer therapy. Since clinical trial results have defined the combination of platinum and taxane as the standard of care in the management of ovarian cancer, here we explored the therapeutic efficacy of the integration of zibotentan with cytotoxic drugs having different modes of action. We found that the combination of zibotentan with cisplatinum as well as zibotentan with paclitaxel was more effective at inhibiting ovarian cancer HEY cell proliferation induced by endogenous ET-1 than were the single agents alone. However, a significantly enhanced efficacy was observed when we combined zibotentan, cisplatinum, and paclitaxel. Accordingly, in HEY xenografts the coadministration of zibotentan with cisplatinum enhanced the efficacy of the cytotoxic drug alone in controlling tumor growth, associated with reduction in proliferation index and microvessel density. Remarkably, the combination of zibotentan with both cisplatinum and paclitaxel was very effective in inhibiting tumor growth, neovascularization, and cell proliferation, representing a preclinical endpoint to guide combination therapy in clinical trials.

scholarly journals Inhibition of Human Malignant Pleural Mesothelioma Growth by Mesenchymal Stromal Cells

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1427
Author(s):  
Valentina Coccè ◽  
Silvia La Monica ◽  
Mara Bonelli ◽  
Giulio Alessandri ◽  
Roberta Alfieri ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Mesenchymal Stromal Cells ◽  
Malignant Pleural Mesothelioma ◽  
Stromal Cells ◽  
Large Scale ◽  
Significant Inhibition ◽  
G1 Arrest ◽  
Pleural Mesothelioma ◽  
Scale Production

Background: Malignant Pleural Mesothelioma (MPM) is an aggressive tumor that has a significant incidence related to asbestos exposure with no effective therapy and poor prognosis. The role of mesenchymal stromal cells (MSCs) in cancer is controversial due to their opposite effects on tumor growth and in particular, only a few data are reported on MSCs and MPM. Methods: We investigated the in vitro efficacy of adipose tissue-derived MSCs, their lysates and secretome against different MPM cell lines. After large-scale production of MSCs in a bioreactor, their efficacy was also evaluated on a human MPM xenograft in mice. Results: MSCs, their lysate and secretome inhibited MPM cell proliferation in vitro with S or G0/G1 arrest of the cell cycle, respectively. MSC lysate induced cell death by apoptosis. The efficacy of MSC was confirmed in vivo by a significant inhibition of tumor growth, similar to that produced by systemic administration of paclitaxel. Interestingly, no tumor progression was observed after the last MSC treatment, while tumors started to grow again after stopping chemotherapeutic treatment. Conclusions: These data demonstrated for the first time that MSCs, both through paracrine and cell-to-cell interaction mechanisms, induced a significant inhibition of human mesothelioma growth. Since the prognosis for MPM patients is poor and the options of care are limited to chemotherapy, MSCs could provide a potential new therapeutic approach for this malignancy.

scholarly journals Nintedanib Is Active in Malignant Pleural Mesothelioma Cell Models and Inhibits Angiogenesis and Tumor Growth In Vivo

2018 ◽  
Vol 24 (15) ◽  
pp. 3729-3740 ◽  
Author(s):  
Viktoria Laszlo ◽  
Zsuzsanna Valko ◽  
Ildiko Kovacs ◽  
Judit Ozsvar ◽  
Mir Alireza Hoda ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Malignant Pleural Mesothelioma ◽  
Pleural Mesothelioma ◽  
Cell Models ◽  
Malignant Pleural Mesothelioma Cell ◽  
Mesothelioma Cell

scholarly journals Pogostemon cablin Triggered ROS-Induced DNA Damage to Arrest Cell Cycle Progression and Induce Apoptosis on Human Hepatocellular Carcinoma In Vitro and In Vivo

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5639
Author(s):  
Xiao-Fan Huang ◽  
Gwo-Tarng Sheu ◽  
Kai-Fu Chang ◽  
Ya-Chih Huang ◽  
Pei-Hsiu Hung ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Growth ◽  
Tumor Growth ◽  
Normal Cells ◽  
Apoptosis Pathway ◽  
Pogostemon Cablin ◽  
Hcc Cells

The purpose of the study was to elucidate the anti-hepatoma effects and mechanisms of Pogostemon cablin essential oils (PPa extract) in vitro and in vivo. PPa extract exhibited an inhibitory effect on hepatocellular carcinoma (HCC) cells and was less cytotoxic to normal cells, especially normal liver cells, than it was to HCC cells, exerting a good selective index. Additionally, PPa extract inhibited HCC cell growth by blocking the cell cycle at the G0/G1 phase via p53 dependent or independent pathway to down regulated cell cycle regulators. Moreover, PPa extract induced the FAS-FASL-caspase-8 system to activate the extrinsic apoptosis pathway, and it increased the bax/bcl-2 ratio and reduced ΔΨm to activate the intrinsic apoptosis pathway that might be due to lots of reactive oxygen species (ROS) production which was induced by PPa extract. In addition, PPa extract presented to the potential to act synergistically with sorafenib to effectively inhibit HCC cell proliferation through the Akt/mTOR pathway and reduce regrowth of HCC cells. In an animal model, PPa extract suppressed HCC tumor growth and prolonged lifespan by reducing the VEGF/VEGFR axis and inducing tumor cell apoptosis in vivo. Ultimately, PPa extract demonstrated nearly no or low system-wide, physiological, or pathological toxicity in vivo. In conclusion, PPa extract effectively inhibited HCC cell growth through inducing cell cycle arrest and activating apoptosis in vitro and in vivo. Furthermore, PPa extract exhibits less toxicity toward normal cells and organs than it does toward HCC cells, which might lead to fewer side effects in clinical applications. PPa extract may be developed into a clinical drug to suppress tumor growth or functional food to prevent HCC initiation or chemoprotection of HCC recurrence.

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