P38 alpha MAP Kinase Inhibitor Inhibits Human Myeloma Cell Growth in Vivo.

Abstract

The p38 MAPK signaling pathway plays an important role in different pathological conditions and specific inhibitors of p38 alpha and beta MAPK block production of major inflammatory cytokines. Human multiple myeloma (MM) is an incurable neoplasm of B cells, and MM disease progression is affected by immunoregulatory elements such as IL-6 and other cytokines. Recent literature indicates that an important function of p38 MAP kinase is the generation of signals of critical value to the control of normal and malignant hematopoiesis by cytokines and growth factors. We therefore examined the effect of a p38 alpha MAP kinase specific inhibitor, SD-282, on human myeloma cell (RPMI8266) tumor growth in immunodeficient beige-nude-xid mouse xenograft plasmacytoma model. Treatment (90 mg/kg/bid by oral gavage) was initiated in mice with palpable tumor size (~200 mm3) as judged by tumor volume. In mice with palpable tumors, 21 days of SD-282 treatment significantly reduced tumor volume. When SD-282 treatment was initiated in mice with pronounced tumor size (~800 mm3) there remained a significant reduction in tumor volume. Histological assessment at the end of dosing from animals administered SD-282 or vehicle demonstrated a significant reduction in tumor volume and number of neoformed microvessels in the SD-282 treatment group. It also significantly reduced HSP27 and p38 expressions in tumor cells.In conclusion, we report that the p38 inhibitor inhibits human myeloma cell growth in vivo via p38 MAP kinase signaling pathway. The current study provides strong in vivo evidence supporting use of p38 inhibitor therapy in patients with multiple myeloma