Targeting wild-type and mutant p53 with small molecule CP-31398 blocks the growth of rhabdomyosarcoma by inducing reactive oxygen species-dependent apoptosis.
Rhabdomyosarcoma (RMS) is a common soft-tissue sarcoma of childhood in need of more effective therapeutic options. The expression of p53 in RMS is heterogeneous such that some tumors are wild-type whereas others are p53 mutant. The small molecule CP-31398 modulates both the wild-type and the mutant p53 proteins. Here, we show that CP-31398 blocks the growth of RMS cells that have either wild-type or mutant p53 status. In wild-type A204 cells, CP-31398 increased the expression of p53 and its downstream transcriptional targets, p21 and mdm2; enhanced the expression of apoptosis-related proteins; and reduced proliferation biomarkers. Flow profiling of CP-31398-treated cells indicated an enhancement in sub-G(0) and G(1) populations. CP-31398 inhibited proliferation in a manner associated with co-induction of SOX9 and p21. Apoptosis induced by CP-31398 occurred with translocation of p53 to mitochondria, leading to altered mitochondrial membrane potential, cytochrome c release, and reactive oxygen species release. In vivo, CP-31398 decreased the growth of tumor xenografts composed of wild-type or mutant p53 tumor cells, increasing tumor-free host survival. Our findings indicate that the ability of CP-31398 to modulate wild-type and mutant p53 results in the inhibition of RMS growth and invasiveness.
Xu
Jianmin
J
Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019, USA.
Timares
Laura
L
Heilpern
Clay
C
Weng
Zhiping
Z
Li
Changzhao
C
Xu
Hui
H
Pressey
Joseph G
JG
Elmets
Craig A
CA
Kopelovich
Levy
L
Athar
Mohammad
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D011743:Pyrimidines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012208:Rhabdomyosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D055758:SOX9 Transcription Factor / Q000096:biosynthesis; D015533:Transcriptional Activation / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D011743:Pyrimidines; D017382:Reactive Oxygen Species; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D016159:Tumor Suppressor Protein p53; D016572:Cyclosporine; D045304:Cytochromes c; C402665:CP 31398