Effect of type 1 insulin-like growth factor receptor targeted therapy on chemotherapy in human cancer and the mechanisms involved

Abstract

Introduction: Chemotherapy is administered only to patients with advanced cancers, typically to modest avail. Hence, the search for innovative approaches to treat cancer is growing rapidly. One such approach involves targeting molecular pathways identified as encouraging tumor growth and maintenance, particularly the type 1 insulin-like growth factor (IGF-1) and its receptor (IGF-1R) pathway that is important in conferring chemoresistance.

Materials and methods: This study focuses on IGF-1R targeted therapy, which will enhance chemotherapy efficacy, through reviewing recent literature from PubMed and Medline databases.

Conclusion: This review examines data and strategies addressing an approach conquering chemoresistance through the combination of IGF-1R targeted therapy and chemotherapy in cancer patients, as well as the mechanisms by which IGF-1R acts as a target. This will impact on future research on treatment selection, thereby improving patient prognosis.

Fig. 1

Mechanisms of action for chemotherapeutic drugs. Illustrates how each class of chemotherapeutic drugs interact with cell function. The lines indicate which section of the cell process each chemotherapeutic is having its effect

Fig. 2

The interplay between p53, MDM2 and IGF-1R. MDM2 can decrease p53 synthesis, but also associate to it causing upregulation of p53. p19 ARF association to MDM2 prevents association to p53. The path taken when chemoresistant p53 mutant is present, is shown in thickened (red) arrows where IGF-1R is upregulated

Fig. 3

Overview of major IGF-1R signaling pathways. Following ligand binding, the two major pathways are activated. The first is the Ras-Raf-MAPK pathway, which is involved in proliferation and differentiation of cells. The second is the PI3K-AKT-mTOR pathway, which is also involved in proliferation and cell growth, but also implicated in cell survival signals to inhibit anti-apoptotic proteins

Fig. 4

IGF-1R pathways leading to development and maintenance of tumor cells. BAD deactivation induces anti-apoptotic protein expression, while the PI3K, MAPK and the 14-3-3 pathways all contribute to sustaining and repairing the cell through cell survival signals