The IGF-1 receptor inhbitor picropodophyllin (PPP) potentiates the anti-myeloma effects of the BH3 mimetic ABT-737.

The role of insulin-like growth factor (IGF-1) in the pathophysiology of mulriple myeloma (MM) has been well established thereby forming an attractive target. Although we previously demonstrated that the IGF-1R inhibitor picopodophyllin (PPP) has potent anti-MM effects, treated MM bearing mice eventually relapsed. To overcome this relapse, combining PPP with other cytotoxic drugs is an attractive approach. The BH3 mimetic ABT-737 shifts the survival/apoptosis balance toward apoptosis by binding the pro-survival proteins Bcl-xL and Bcl-2, but not to Mcl-1. In MM, elevated expression of Mcl-1 has extensively been shown to contribute to drug resistance. Consequently, ABT-737 has potent anti-MM activity but only on a subset of human cell lines. Interestingly, a protective effect of IL-6 and bone marrow stromal cells on the ABT-737-induced apoptosis was reported. This suggests that it would be beneficial to combine ABT-737 wit PPP. Here, we investigated the combination of ABT-737 and PPP in human MM cell lines and in the murine 5T33MM model. Both agents alone were found to decrease viability and induce apoptosis, dose and time dependently. Moreover, combination of both agents synergistically decreased cell viability and induced apoptosis compared to single agent treatment. Preliminar results also confirm this synergistic anti-MM activity in primary human MM samples. Mechanistically, western blot analysis revealed that combination treatment results in enhanced cleavage of caspartase 3, 9 and PARP, increased expression of the pro-apoptotic protein Noxa and reduced expression of Mcl-1 and Bcl-2. Moreover, while the CD138+ 5T33MM subpopulation was more sensitive to ABT-737, both subpopulations were targeted equally when treated with the combination. Lastly, the 5T33MM model was used to evaluate the in vivo anti-MM activity of PPP and/or ABT-737 in prophylactic setting. Combinatory treatment significantly decreased BM tumour burden and prolonged overall survival of the combination treated mice (p=0.001). In conclusion, the combination of PPP and ABT-737 has synergistic anti-MM activity and may thus be a promising treatment option for MM.