Selective Up-Regulation of Tumor Suppressor Gene Retinoblastoma by Bisacridine Derivative Through Gene Promoter Quadruplex Structures for Cancer Treatment.

The retinoblastoma (RB) gene is an important tumor suppressor gene with a higher mutation frequency than other tumor suppressor genes. The mutation or inactivation of RB has been found in various cancers. The discovery of small molecules to promote RB expression is an effective anti-cancer strategy. Special DNA secondary structures with G-quadruplex and i-motif on the RB promoter could act as "molecular switches" for gene transcriptional regulation and are potentially important targets for the development of new anti-cancer drugs. After extensive screening, we found that the bisacridine derivative A06 had selective binding and destabilization for both the G-quadruplex and i-motif on the RB promoter, which significantly up-regulated RB gene transcription and translation, resulting in the inhibition of tumor cell proliferation and metastasis. A06 exhibited potent anti-tumor activity on Hela cells and strongly suppressed tumor growth on the Hela xenograft mice model without significant toxicity. In comparison, A02 exhibited strong binding and destabilization to the RB promoter G-quadruplex only, which showed a much weaker effect than A06 on regulating RB expression and producing anti-tumor activity. As we know, this is the first study for up-regulating a tumor suppressor gene through destabilization of both the G-quadruplex and i-motif on the gene promoter, which provides a new strategy for innovative anti-cancer drug discovery and development.