Deregulated ribosomal RNA synthesis is associated with uncontrolled cancer cell proliferation. RNA polymerase (Pol) I, the multiprotein complex that synthesizes rRNA, is activated widely in cancer. CX-5461, a potent small-molecule inhibitor of rRNA synthesis in cancer cells, selectively inhibits Pol I with IC50 value of 142 nM in the HCT-116 cells. The IC50 for rRNA synthesis for the BJ-hTert normal cell line of 74 nM correlated well with the IC50 values of the solid tumor cell lines (IC50 = 142, 113, and 54 nM, respectively) illustrating that CX-5461 can equivalently inhibit Pol I transcription in cancer and normal cells, but the normal cells can tolerate reductions in rRNA synthesis without induction of cell death. Treatment with 300 nM CX-5461 for 24 hours caused a significant increase from 15% ± 3% to 67% ± 2% in LC3B-II staining (P = 0.0041) in A375 and from 19% ± 2% to 62% ± 3% in LC3B-II staining (P = 0.002) in MIA PaCa-2 cells (LC3B-II, a known marker of autophagy). In addition to autophagy, CX-5461 (300 nM; 24 hours) was able to induce senescence in both cell lines. In two murine xenograft models of human cancers, MIA PaCa-2 and A375, CX-5461 was administered orally (50 mg/kg) either once daily or every 3 days. CX-5461 demonstrated significant MIA PaCa-2 TGI (tumor growth inhibition) equal to 69% on day 31. Likewise, CX-5461 demonstrated significant A375 TGI equal to 79% on day 32[5].
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