Inhibition of IGF-1 Signalling Enhances the Apoptotic Effect of AS602868, an IKK2 Inhibitor, in Multiple Myeloma Cell Lines

Abstract

Multiple myeloma (MM) is a B cell neoplasm characterized by bone marrow infiltration with malignant plasma cells. IGF-1 signalling has been explored as a therapeutic target in this disease. We analyzed the effect of the IKK2 inhibitor AS602868, in combination with a monoclonal antibody targeting IGF-1 receptor (anti-IGF-1R) in human MM cell lines. We found that anti-IGF-1R potentiated the apoptotic effect of AS602868 in LP1 and RPMI8226 MM cell lines which express high levels of IGF-1R. Anti-IGF-1R enhanced the inhibitory effect of AS602868 on NF-κB pathway signalling and potentiated the disruption of mitochondrial membrane potential caused by AS602868. These results support the role of IGF-1 signalling in MM and suggest that inhibition of this pathway could sensitize MM cells to NF-κB inhibitors.

PI3K inhibitor LY294002 inhibits activation of the Akt/mTOR pathway induced by an oncolytic adenovirus expressing TRAIL and sensitizes multiple myeloma cells to the oncolytic virus

“…It is noteworthy that RPMI-8226 cells were more sensitive to ZD55-TRAIL-induced cell death than MM1.S and MM1.R cells. This result is consistent with a previous finding that RPMI-8226 cells express more IGF-1R than MM.1S and U266 cells, and that the cytotoxic effect of anti-IGF-1R is more effective on MM cells with a high level of IGF-1R (20). Our data also showed that ZD55-TRAIL-mediated apoptosis and cell growth inhibition were not reversed by IGF.…”

“…Recent studies suggest that the inhibition of IGF-1R decreases cell proliferation. Furthermore, combinations of multiple drugs such as the IKK2 inhibitor AS602868 and bortezomib with agents intervening in the IGF-1R pathway were found to result in enhanced apoptosis and reversal of drug-resistance (19,20,38), suggesting that targeting the IGF-1/IGF-1R axis is a promising approach for the treatment of MM. Our results confirm the inhibitory effect of ZD55-TRAIL on the expression of IGF-1R in RPMI-8226 cells.…”

“…It was recently reported that signaling through the IGF-1/IGF-1R axis contributes to acquired bortezomib resistance (19), and that inhibition of IGF-1R enhances cell death of MM cells induced by an IKK2 inhibitor (20). In the present study, we aimed to ascertain whether ZD55-TRAIL suppresses IGF-1R expression in RPMI-8226 cells.…”

Sphingosine Kinase-1 Protects Multiple Myeloma from Apoptosis Driven by Cancer-Specific Inhibition of RTKs

“…I-kB kinase (IKK) inhibitors promote multiple myeloma cell apoptosis, and inhibition of IGF1 signaling enhances this effect (39). Therefore, inhibiting IGF1 signaling could enhance the use of IKK inhibitors for multiple myeloma treatment.…”

Long Intergenic Noncoding RNAs Mediate the Human Chondrocyte Inflammatory Response and Are Differentially Expressed in Osteoarthritis Cartilage

“…Since previous studies have shown that NF-kB activity can regulate the expression of lncRNAs, we then also examined the effect of pharmacologic inhibition of IKK-2 on the IL-1b-stimulated production of CILinc01 and CILinc02. To this end we used TPCA-1, a known IKK-2 inhibitor (20,32,33). In cellfree enzymatic assays, TPCA-1 displays 22-fold selectivity for IKK-2 over IKK-1 and a .550-fold selectivity over other kinases, including MAP kinases and JNK kinases (32), though a recent study showed that in non-small cell lung cancer cell lines TPCA-1 also inhibited STAT-3 phosphorylation (34).…”