Combined inhibition of IGFR signaling enhances the growth inhibitory and apoptosis-inducing effects of gefitinib, suggesting that this approach could be useful to overcome the primary resistance to EGFR-TKIs in lung cancer.

The radioprotective effects of granulocyte colony-stimulating factor (GCSF) were further investigated with respect to the testicular system. Recombinant human GCSF (100 μg kg(-1) body weight/day) was administrated to male C3H/HeN mice by subcutaneous injection for three consecutive days before pelvic irradiation (5 Gy) and histopathological parameters were assessed at 12 h and 21 days post-irradiation (pi). The GCSF protected the germ cells from radiation induced- apoptosis (P < 0.01 vs. irradiated group at 12 h pi). GCSF remarkably attenuated radiation-induced reduction in testis weight, seminiferous tubular diameter, seminiferous epithelial depth and sperm head count in the testes (P < 0.05 versus irradiated group at 21 days pi). Repopulation index and stem cell survival index of the seminiferous tubules were increased in the GCSF-treated group when compared with the radiation group (P < 0.01). The frequency of abnormal sperm in the GCSF group was lower than that in the irradiated group at 21 days pi (P < 0.01). The decrease in the sperm count and in sperm liability in the epididymis caused by irradiation was counteracted by GCSF. The present study suggests that GCSF protects from radiation-induced testicular dysfunction via an anti-apoptotic effect and recovery of spermatogenesis.

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) produce an initially dramatic response in lung cancer patients harboring a mutation in the EGFR gene, development of acquired resistance is almost inevitable. A secondary mutation of threonine 790 (T790M) is associated with approximately half of the cases of acquired resistance. This study investigated whether the addition of silibinin to therapy with gefitinib or erlotinib could overcome T790M-mediated drug resistance considering that silibinin has various antitumor effects, including EGFR modulation. Silibinin selectively reduced the activity of the EGFR family (EGFR, ErbB2, and ErbB3) through the inhibition of receptor dimerization in lung cancer cells with EGFR mutations, but not in those harboring the wild type. In primary and acquired resistant cells with T790M, addition of silibinin enhanced the ability of EGFR-TKIs to downregulate EGFR signals and to inhibit cell growth. Similarly, the combination of silibinin and erlotinib effectively suppressed tumor growth in erlotinib resistance-bearing PC-9 xenografts. The results indicate that the addition of silibinin to EGFR-TKIs is a promising strategy to overcome T790M-mediated drug resistance. Mol Cancer Ther; 9(12); 3233-43. Ó2010 AACR.