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Proc. National Academy of Science,
USA, Vol. 95, pp. 162-166, Jan 1998, Cell Biology.
Siegel DS, Zhang X, Feinman R, Teitz T, Zelenetz A, Richon VM, Rifkind RA, Marks PA, Michaeli J
Program of Cell Biology, The University of Arkansas, Little Rock, AR 72205, USA.
Multiple myeloma (MM) is a B cell
malignancy characterized by the expansion of monoclonal Ig-secreting plasma
cells with low proliferative activity. It is postulated that inhibition of
physiologic cell death is an underlying factor in the pathophysiology of MM. The
development of chemoresistance is a common feature in patients with MM. In the
present studies, hexamethylene bisacetamide (HMBA), a hybrid polar compound that
is a potent inducer of terminal differentiation of various transformed cells, is
shown to inhibit the growth of several human myeloma cell lines (ARP-1, U266,
and RPMI 8226), including doxorubicin-resistant RPMI 8226 variants that
overexpress the multidrug-resistance gene, MDR-1, and its product,
p-glycoprotein. In addition to growth arrest and suppression of clonogenicity,
HMBA induces apoptosis both in freshly isolated human myeloma cells and in cell
lines, as determined by morphologic alterations, cell cycle distribution and
endonucleosomal DNA fragmentation. Further, HMBA decreases BCL-2 protein
expression in myeloma cells within 12-48 hr. Overexpression of BCL-2 protein in
ARP-1 cells confers resistance to HMBA-induced apoptosis. Taken together, these
data suggest that HMBA is a potent inducer of apoptosis in human myeloma cells,
which may act through suppressing the anti-apoptotic function of the bcl-2 gene.
HMBA, and related hybrid polar compounds, may prove useful in the management of
this presently incurable disease.