Positive Feedback Regulation of Poly(ADP-ribose) Polymerase 1 and the DNA-PK Catalytic Subunit Affects the Sensitivity of Nasopharyngeal Carcinoma to Etoposide

Etoposide (VP-16) is used for the treatment of various cancers, including nasopharyngeal carcinoma (NPC); however, cancers develop resistance to this agent by promoting DNA repair. The DNA-PK (DNA-PKcs) catalytic subunit and poly­(ADP-ribose) polymerase 1 (PARP1) mediate acquired resistance and poor survival in NPC cells exposed to DNA damaging agents. DNA repair can alter the sensitivity of NPC cells to DNA damaging agents, and these two enzymes function concomitantly in response to DNA damage in vivo. Therefore, we explored the relationship between DNA-PKcs and PARP1, which may affect NPC cell survival by regulating DNA repair after VP-16 treatment. We performed quantitative real-time polymerase chain reaction, western blotting, and enzyme-linked immunoassays and found that DNA-PKcs knockdown downregulated the PARP1 and PAR expression. Conversely, PARP1 knockdown reduced DNA-PKcs activity, indicating the mutual regulation between DNA-PKcs and PARP1 in VP-16-induced DNA repair. Moreover, a combination treatment with olaparib (a PARP1 inhibitor) and NU7441 (a DNA-PKcs inhibitor) sensitized NPC cells to VP-16 in vitro and in vivo, suggesting that the combined treatment of olaparib, NU7441, and a DNA-damaging agent may be a successful treatment regimen in patients with NPC

Supplementary Figure S1 from Dual Inhibition of Bcr-Abl and Hsp90 by C086 Potently Inhibits the Proliferation of Imatinib-Resistant CML Cells

Supplementary Figure S1. C086 induces apoptosis in imatinib-sensitive and -resistant CML cells.</p

Supplementary Figure S4 from Dual Inhibition of Bcr-Abl and Hsp90 by C086 Potently Inhibits the Proliferation of Imatinib-Resistant CML Cells

Supplementary Figure S4. C086 potently inhibits the growth of human leukemia progenitor/stem cells.</p

Supplementary Figure S3 from Dual Inhibition of Bcr-Abl and Hsp90 by C086 Potently Inhibits the Proliferation of Imatinib-Resistant CML Cells

Supplementary Figure S3. Effects of C086 on cell cycle progression.</p

Supplementary Figure S5 from Dual Inhibition of Bcr-Abl and Hsp90 by C086 Potently Inhibits the Proliferation of Imatinib-Resistant CML Cells

Supplementary Figure S5. C086 treatment does not affect the engraftment of normal bone marrow cells in NOD-SCID mice.</p

Supplementary Figure S6 from Dual Inhibition of Bcr-Abl and Hsp90 by C086 Potently Inhibits the Proliferation of Imatinib-Resistant CML Cells

Supplementary Figure S6. The scheme of origins of LSCs and the effects of C086 on LSCs via eradicate leukemia cells at different mature state.</p

Supplementary Methods and Materials, Figure Legend from Dual Inhibition of Bcr-Abl and Hsp90 by C086 Potently Inhibits the Proliferation of Imatinib-Resistant CML Cells

Supplementary Methods and Materials, Figure Legend</p

Supplementary Figure S2 from Dual Inhibition of Bcr-Abl and Hsp90 by C086 Potently Inhibits the Proliferation of Imatinib-Resistant CML Cells

Supplementary Figure S2. C086 triggers the mitochondrial pathway of apoptosis in CML cells.</p