CBP501 is an anti-
cancer drug candidate which has been shown to increase cis-diamminedichloro-
platinum (II) (CDDP) uptake into
cancer cell through
calmodulin (CaM) inhibition. However, the effects of
CBP501 on the cells in the tumor microenvironment have not been addressed. Here, we investigated new aspects of the potential anti-
tumor mechanism of action of
CBP501 by examining its effects on the macrophages. Macrophages contribute to
cancer-related
inflammation and sequential production of
cytokines such as
IL-6 and TNF-α which cause various biological processes that promote
tumor initiation, growth and
metastasis (1). These processes include the epithelial to mesenchymal transition (EMT) and cancer stem cell (CSC) formation, which are well-known, key events for
metastasis. The present work demonstrates that
CBP501 suppresses
lipopolysaccharide (LPS)-induced production of
IL-6,
IL-10 and TNF-α by macrophages.
CBP501 also suppressed formation of the
tumor spheroids by culturing with
conditioned medium from the LPS-stimulated macrophage cell line RAW264.7. Moreover,
CBP501 suppressed expression of ABCG2, a marker for CSCs, by inhibiting the interaction between
cancer cells expressing
VCAM-1 and macrophages expressing
VLA-4. Consistently with these results,
CBP501 in vivo suppressed
metastases of a tumor cell line, 4T1, one which is insensitive to combination treatment of
CBP501 and CDDP in vitro. Taken together, these results offer potential new, unanticipated advantages of
CBP501 treatment in anti-
tumor therapy through a mechanism that entails the suppression of interactions between macrophages and
cancer cells with suppression of sequential CSC-like cell formation in the tumor microenvironment.