Multiple myeloma (MM) is a clonal plasma cell
malignancy, which is currently incurable. Therefore, new mono- or combined
therapy treatment regimens in the early and advanced phases of MM are urgently needed to combat this disease. Recently,
p38 mitogen-activated protein kinase (MAPK) has been implicated as playing an important role in MM. Therefore, the effect of a p38alpha-selective MAPK inhibitor,
SCIO-469 (indole-5-carboxamide, ATP-competitive inhibitor), or its structural analog,
SD-282 (indole-5-carboxamide, ATP-competitive inhibitor) was examined in mouse xenograft models of MM using human RPMI-8226 or H-929
plasmacytoma inocula. Oral treatment with
SCIO-469 (10, 30, 90 mg/kg) twice daily was initiated in mice with palpable
tumors of RPMI-8226 origin, a condition that mimics early human myeloma disease. In mice with palpable
tumors, 14 days of
SCIO-469 treatment significantly reduced RPMI-8226
tumor growth in a dose-dependent manner. A significant dose-dependent reduction in RPMI-8226
tumor growth was also observed when
SCIO-469 oral treatment at doses of 10, 30 and 90 mg/kg twice daily was initiated in mice with
tumors of pronounced size, a condition that mimics advanced human myeloma disease. In a similar set of studies employing the
SCIO-469 analogue
SD-282 at 90 mg/kg/bid orally, histological assessment at the end of the study demonstrated a significant reduction in RPMI-8226
tumor growth and angiogenesis.
SD-282 treatment was additionally shown to significantly reduced expression of heat-shock protein-27 (HSP-27) and phospho-p38 in the
tumor cells. Furthermore, co-administration of
SCIO-469 with
dexamethasone elicited antitumor properties in
dexamethasone-sensitive H-929
tumors at much lower than the typically effective doses of
dexamethasone, suggesting its potential for combined
therapy. In conclusion, p38 inhibitors reduced human myeloma cell growth in vivo both at early and advanced phases of the disease. The current study also provides evidence of potential for co-
therapy with
dexamethasone.