Combined treatment with inhibitors of ErbB Receptors and Hh signaling pathways is more effective than single treatment in reducing the growth of malignant mesothelioma both in vitro and in vivo

Abstract

Malignant mesothelioma (MM) is a rare orphan aggressive neoplasia with low survival rates. Among the other signaling pathways, ErbB receptors and Hh signaling are deregulated in MM. Thus, molecules involved in these signaling pathways could be used for targeted therapy approaches. The aim of this study was to evaluate the effects of inhibitors of Hh- (GANT-61) and ErbB receptors (Afatinib)-mediated signaling pathways, when used alone or in combination, on growth, cell cycle, cell death and autophagy, modulation of molecules involved in transduction pathways, in three human MM cell lines of different histotypes. The efficacy of the combined treatment was also evaluated in a murine epithelioid MM cell line both in vitro and in vivo. This study demonstrated that combined treatment with two inhibitors counteracting the activation of two different signaling pathways involved in neoplastic transformation and progression, such as those activated by ErbB and Hh signaling, is more effective than the single treatments in reducing MM growth in vitro and in vivo. This study may have clinical implications for the development of targeted therapy approaches for MM.

Antitumoral effects of Bortezomib in malignant mesothelioma: evidence of mild endoplasmic reticulum stress in vitro and activation of T cell response in vivo

“…Receptor tyrosine kinases of the ErbB family are overexpressed in MM. Their activation is linked to the MAP (Mitogen-Activated Protein) kinase and the phosphoinositide 3-kinase/AKT signal transduction cascades [ 32 , 33 ]. Therefore, the expression of EGFR and ErbB2, as well as the expression and activation of the downstream pro-survival signaling effectors ERK1/2, AKT and p38 were analyzed by Western blotting (Fig.…”

“…Considering the involvement of aberrant ErbB signaling in MM [ 32 , 55 ] and the evidence that ErbB receptors levels are regulated, among the other mechanisms, via proteasomal degradation [ 56 , 57 ], we also investigated whether Bor treatment could affect the expression of EGFR and ErbB2 and the activation of downstream pro-survival signaling effectors. The treatment resulted in reduced levels of at least one among EGFR and ErbB2 receptors in all cell lines except MM-F1.…”

“…In the present study, we used a different model established in immunocompetent C57BL/6 mice, in which the growth of i.p. transplanted #40a MM cells reproducibly leads to ascites formation [ 32 , 64 – 66 ]. The results obtained using this model confirm the ability of Bor to suppress MM growth in vivo and extend mice survival.…”

“…The percentage survival of the cultures treated with Bor was calculated by normalization of their O.D. values to those of the control cultures treated with DMSO [ 32 ]. The experiments were performed in triplicate and repeated three times.…”

Dauricine attenuates Oct4/sonic hedgehog co‐activated stemness and induces reactive oxygen species‐mediated mitochondrial apoptosis via AKT/β‐catenin signaling in human neuroblastoma and glioblastoma stem‐like cells

“…We constructed the Oct4 overexpressed models in neuroblastoma SH‐SY5Y and glioblastoma T98‐G cells, and the cells were then stimulated by Shh. In the colony formation assay, this combination was very effective at increasing tumor cell growth, it probably was due to Hh signaling activated by the binding of Hh ligand and Shh, which play a pivotal role in the tumor regulatory processes including proliferation, migration, and differentiation (Bei et al, 2022). Following this we cultured the cells in neural stem cell medium, the Oct4/Shh co‐activation significantly accelerated the formation of tumor spheres.…”