Insulin-like growth factor-I receptor tyrosine kinase inhibitor cyclolignan picropodophyllin inhibits proliferation and induces apoptosis in multidrug resistant osteosarcoma cell lines

Insulin-like growth factor-I receptor (IGF-IR) is an important mediator of tumor cell survival and shows prognostic significance in sarcoma. To explore potential therapeutic strategies for interrupting signaling through this pathway, we assessed the ability of cyclolignan picropodophyllin (PPP), a member of the cyclolignan family, to selectively inhibit the receptor tyrosine kinase activity of IGF-IR in several sarcoma cell line model systems. Of the diverse sarcoma subtypes studied, osteosarcoma cell lines were found to be particularly sensitive to IGF-IR inhibition, including several multidrug resistant osteosarcoma cell lines with documented resistance to various conventional anticancer drugs. PPP shows relatively little toxicity in human osteoblast cell lines when compared with osteosarcoma cell lines. These studies show that PPP significantly inhibits IGF-IR expression and activation in both chemotherapy-sensitive and chemotherapy-resistant osteosarcoma cell lines. This inhibition of the IGF-IR pathway correlates with suppression of proliferation of osteosarcoma cell lines and with apoptosis induction as measured by monitoring of poly(ADP-ribose) polymerase and its cleavage product and by quantitative measurement of apoptosis-associated CK18Asp396. Importantly, PPP increases the cytotoxic effects of doxorubicin in doxorubicin-resistant osteosarcoma cell lines U-2OS(MR) and KHOS(MR). Furthermore, small interfering RNA down-regulation of IGF-IR expression in drug-resistant cell lines also caused resensitization to doxorubicin. Our data suggest that inhibition of IGF-IR with PPP offers a novel and selective therapeutic strategy for ostosarcoma, and at the same time, PPP is effective at reversing the drug-resistant phenotype in osteosarcoma cell lines.