Synergistic enhancement of apoptosis by DNA- and cytoskeleton-damaging agents: A basis for combination chemotherapy of cancer

Actinomycin D (AD)-induced apoptosis in CMK-7 cells is greatly accelerated by cytoskeletal poisons such as colcemid (CL) and cytochalasin D (CD). This phenomenon is important in the combination chemotherapy of cancer so that its generality was investigated. Four human leukemia and two human solid tu mor cell lines were treated with combinations of one DNA-damaging agent (AD , mitomycin C (MMC), or etoposide (VP-16) ] and one cytoskeletal poison [CL , CD, or vinblastine (VBL)]. The apoptosis was monitored by assaying caspas e-3 activity and the DNA cleavage ratio. The caspase-3 activation in all le ukemia and HeLa S3 cell lines was, except for a few cases, 1.3-to 6.0-fold enhanced by combinations of the DNA-damaging agent with a cytoskeletal pois on. The DNA cleavage ratio as well as the dead cell ratio was also 1.4-to 2 3.7 fold enhanced in CMK-7, U-937, HeLa S3, and Colo320 DM cell lines by th e combinations of AD with CL, CD, or VBL. The combination index for caspase -3 activation by AD and CL in U-937 cells was smaller than 1 at Fa of more than 0.03. Thus, apoptosis in many tumor cell lines is synergistically enha nced by various combinations of DNA- and cytoskeleton-damaging agents.