Elimination of extrachromosomal c-myc genes by hydroxyurea induces apoptosis

Hydroxyurea (HU) increases extrachromosomal DNA elimination in tumor cell l ines. The c-myc oncogene is one of the many relevant amplified genes contai ned within the extrachromosomal DNA compartment. Spontaneous loss of amplif ied copies of c-myc induces terminal differentiation and apoptosis in the h uman HL-60 leukemia cell lines. In the present study, we evaluate HU's abil ity to induce apoptosis by eliminating extrachromosomally located c-myc onc ogene in human tumor cell lines. The consequences of eliminating extrachrom osomal DNA by HU were explored in two different cell lines using the TdT as say and acridine orange/ethidium bromide labeling. COLO 320 clone 3 and COL O 320 clone 21 cell lines contain the same number of amplified copies of c- myc oncogene, but located respectively on extrachromosomal DNA, and intrach romosomally in homogeneously staining regions. HU induced apoptosis in the COLO 320 clone 3 cell line by a time and concentration dependent mechanism but could not induce apoptosis in the COLO 320 clone 21 cell line. These re sults suggested that HU-induced apoptosis in COLO 320 cell lines depends on elimination of extrachromosomal amplified copies of the c-myc oncogene. Th e ability of HU to eliminate extrachromosomally amplified copies of the c-m yc oncogene and to induce apoptosis should be considered when targeting mal ignancies with amplification of the c-myc oncogene in an extrachromosomal s ite.