Abstract
The ribozyme-sensitive element NHE-III1 in the P1 promoter region of the important proto-oncogene c-myc contains many guanine (G)-rich sequences. Induction and stabilization of the G-quadruplex formed by NHE-III1 can downregulate c-myc expression. In the present study, we found that QPB-15e, a quinazoline derivative designed and synthesized by our laboratory, binds to and stabilizes the c-myc G-quadruplex in vitro, thereby inhibiting double-stranded DNA replication, downregulating c-myc gene expression and arresting cancer cell proliferation. PCR termination experiments showed that QPB-15e blocked double-stranded DNA replication by inducing or stabilizing the c-myc G-quadruplex. FRET-melting further confirmed that QPB-15e improved the stability of the G-quadruplex, and CD spectroscopy indicated that the compound interacted directly with the G-rich sequence. In competitive dialysis experiments, QPB-15e bound preferentially to quadruplex DNA in various structures, especially the G-quadruplex within the c-myc promoter region. Moreover, QPB-15e reduced the weights and volumes of tumors transplanted into nude mice. These findings strongly suggest that QPB-15e is a c-myc G-quadruplex ligand with anti-tumor properties, and may be efficacious for treating cancer in humans.
Highlights
The human c-myc oncogene is a pluripotent cytokine and a key regulator of many physiological processes, including cell-cycle control, protein synthesis, apoptosis and cell adhesion [1]
We found that QPB-15e, a quinazoline derivative designed and synthesized by our laboratory, binds to and stabilizes the c-myc G-quadruplex in vitro, thereby inhibiting double-stranded DNA replication, downregulating c-myc gene expression and arresting cancer cell proliferation
fluorescence resonance energy transfer (FRET)-melting further confirmed that QPB-15e improved the stability of the G-quadruplex, and Circular dichroism (CD) spectroscopy indicated that the compound interacted directly with the G-rich sequence
Summary
The human c-myc oncogene is a pluripotent cytokine and a key regulator of many physiological processes, including cell-cycle control, protein synthesis, apoptosis and cell adhesion [1]. C-myc transcription is primarily regulated by a 27-base G-rich sequence in the NHE III1 (nuclease hypersensitivity element III1) region [12,13]. This sequence is located upstream (−142 to −115 bp) of the P1 promoter in the human c-myc oncogene and controls 85–90% of c-myc transcription [14]. This tract can form specific G-quadruplex structures enhanced by G-quadruplex-interactive ligands, leading to c-myc downregulation in human tumor cells [15,16]. Small molecules that can selectively bind to and stabilize the c-myc G-quadruplex are likely to be effective therapeutics for cancer treatment
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