The insulin‐like growth factor‐I receptor inhibitor picropodophyllin causes tumor regression and attenuates mechanisms involved in invasion of uveal melanoma cells

Abstract

Purpose: Uveal melanoma has a high mortality rate due to a high incidence of metastasis (up to 50%) which preferentially occurs in the liver. Conventional chemotherapy being the only therapeutic option today against metastatic uveal melanoma, has not proved to be effective. Therefore, new molecular targets important for malignant phenotype of uveal melanoma have to be found to design efficient pharmacologic agents. Experimental Design: We previously reported data indicating that the insulinlike growth factor-1 receptor (IGF-IR) is a metastasis predictor as well as a therapeutic target for uveal melanoma. In the present study, we made use of the cyclolignan picropodophyllin (PPP), which is an inhibitor of the IGF-IR. Result: We showed that PPP efficiently block growth and viability of uveal melanoma cells in cultures and causes tumor regression in xenografted mice. In addition, treatment with PPP inhibited several mechanism involved in metastasis, including tumor cells adhesion to extracellular matrix proteins, activity and expression of matrix metalloproteinase 2, and cell migration as well as invasion through basement membranes and endothelial cell layer. Furthermore, PPP significantly delayed established of uveal melanoma tumor and drastically reduced the indence of liver metastasis in mice. Conclusions: Our data suggest that IGR-IR is crucial for growth and survival as well as invasion and metastasis of uveal melanoma cells. Targeting this receptor may therefore comprise a strategy to treat ongoing disease (today incurable) as well as a strategy to prevent development of metastases in patients with primary disease.

The dichotomy of the Insulin-like growth factor 1 receptor: RTK and GPCR: friend or foe for cancer treatment?

“…Among the second category of the IGF-1R kinase inhibitors (TKIs), the cyclolignan picropodophyllin (PPP), originally described as inhibiting the IGF-1R [38] and inducing tumour regression in xenografted mice [3,10,21,[29][30][31]37,54,59,68,89,92,94,110,116,134,143,146,155], also triggers IGF-1R downregulation [144] raising the question of how the receptor is downregulated when its kinase activity is inhibited via either strategy? This contradiction was recently investigated for the case of anti-IGF-1R antibody (Figitumumab) induced receptor degradation [157].…”

Picropodophyllin inhibits proliferation and survival of diffuse large B-cell lymphoma cells

“…PPP, being at least 50 times less effective than PPT at inhibiting microtubule assembly [13], has been launched as a potent and selective inhibitor of the IGF-1R [14] by specifically blocking phosphorylation of the tyrosine residue Tyr1136 within the activation loop of the IGF-1R beta subunit [15]. Via inhibition of the IGF-1R, PPP has been demonstrated to reduce phosphorylation of the downstream targets AKT and/or ERK1/2 [5,6,14,16,17] and also to induce apoptosis of malignant cells as well as tumor regression in different tumor models [6,14,[16][17][18][19].…”

Transcriptional profiling of human uveal melanoma from cell lines to intraocular tumors to metastasis

“…Two separate studies have recently demonstrated that the expression of the insulin like growth factor 1 (IGF-1) receptor in uveal melanoma patients correlated with poor prognosis [21,22]. In addition, the inhibition of the IGF-1 receptor by cyclolignan picropodophyllin was shown to inhibit growth, motility, and invasion of uveal melanoma cells and cause tumor regression in a xenograft mouse model [22].…”