HEXAMETHYLENE BISACETAMIDE INDUCES PROGRAMMED CELL-DEATH (APOPTOSIS) AND DOWN-REGULATES BCL-2 EXPRESSION IN HUMAN MYELOMA CELLS

Multiple myeloma (MM) is a B cell malignancy characterized by the expa nsion of monoclonal Ig-secreting plasma cells with low proliferative a ctivity, 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 prese nt studies, hexamethylene bisacetamide (HMBA), a hybrid polar compound that is a potent inducer of terminal differentiation of various trans formed cells, is shown to inhibit the growth of several human myeloma cell lines (ARP-1, U266, and RPMI 8226), including doxorubicin-resista nt RPMI 8226 variants that overexpress the multidrug-resistance gene, MDR-1, and its product, p-glycoprotein. In addition to growth arrest a nd suppression of clonogenicity, HMBA induces apoptosis both in freshl y isolated human myeloma cells and in cell lines, as determined hy mor phologic alterations, cell cycle distribution and endonucleosomal DNA fragmentation, Further, HMBA decreases BCL-2 protein expression in mye loma cells within 12-48 hr, Overexpression of BCL-2 protein in ARP-1 c ells confers resistance to HMBA-induced apoptosis, Taken together, the se data suggest that HMBA is a potent inducer of apoptosis in human my eloma cells, which may act through suppressing the anti-apoptotic func tion of the bcl-2 gene, HMBA, and related hybrid polar compounds, may prove useful in the management of this presently incurable disease.