G-Quadruplex Stabilizer 3,6-Bis(1-Methyl-4-Vinylpyridinium)Carbazole Diiodide Induces Accelerated Senescence and Inhibits Tumorigenic Properties in Cancer Cells

Abstract

Carbazole derivatives that stabilized G-quadruplex DNA structure formed by human telomeric sequence have been designed and synthesized. Among them, 3,6-bis(1-methyl-4-vinylpyridinium)carbazole diiodide (BMVC) showed an increase in G-quadruplex melting temperature by 13°C and has a potent inhibitory effect on telomerase activity. Treatment of H1299 cancer cells with 0.5 Mmol/L BMVC did not cause acute toxicity and affect DNA replication; however, the BMVC-treated cells ceased to divide after a lag period. Hallmarks of senescence, including morphologic changes, detection of senescence-associated B-galactosidase activity, and decreased bromodeoxyuridine incorporation, were detected in BMVC-treated cancer cells. The BMVCinduced senescence phenotype is accompanied by progressive telomere shortening and detection of the DNA damage foci, indicating that BMVC caused telomere uncapping after long-term treatments. Unlike other telomerase inhibitors, the BMVC-treated cancer cells showed a fast telomere shortening rate and a lag period of growth before entering senescence. Interestingly, BMVC also suppressed the tumor-related properties of cancer cells, including cell migration, colony-forming ability, and anchorage-independent growth, indicating that the cellular effects of BMVC were not limited to telomeres. Consistent with the observations from cellular experiments, the tumorigenic potential of cancer cells was also reduced in mouse xenografts after BMVC treatments. Thus, BMVC repressed tumor progression through both telomere-dependent and telomereindependent pathways. (Mol Cancer Res 2008;6(6):955 -64)

Inhibition of Cancer Cell Migration and Invasion through Suppressing the Wnt1-mediating Signal Pathway by G-quadruplex Structure Stabilizers

“…3B). Under the BMVC or BMVC4 conditions, no apparent cytotoxic effect was observed for up to 6 days (19,20). These results indicate that G-quadruplex stabilizers could reduce the expression of WNT1.…”

“…Previously, we characterized two carbazole derivatives, BMVC and BMVC4 ( Fig. 2A), that bound and stabilized the G-quadruplex structures formed by both human telomeric DNA sequences and the quadruplex-forming sequence located at the c-myc promoter (19,20). These two compounds were employed here to determine whether they could bind and stabilize the G-quadruplex structure formed by the G-rich sequence of WNT1 promoter.…”

“…Previously, we have developed two carbazole derivatives, 3,6-bis(1-methyl-4-vinylpyridinium) carbazole diiodide (BMVC) 4 and 3,6-bis(4-methyl-2-vinylpyrazinium) carbazole diiodide (BMVC4), that bind to G-quadruplex structure formed by telomeric DNA sequences, inhibit telomerase activity, cause telomere shortening, and induce cancer cells into senescence (19,20). The binding of BMVC and BMVC4 to G-quadruplex structures, however, is not limited to telomeres as they also target a quadruplex forming sequence located at the promoter region of c-myc to repress its expression.…”

Mechanism of the Antiproliferative Activity of Some Naphthalene Diimide G-Quadruplex Ligands

“…Other Gquadruplex ligands, such as TMPyP4, cause G2/M phase arrest in MCF7 cells at subcytotoxic concentrations (Izbicka et al, 1999). Multiple effects on cell-cycle progression, such as activation of S-phase checkpoint and increase of M-phase, can also occur (Pennarun et al, 2005), as well as S-and G2/M phase arrest (Leonetti et al, 2004;Huang et al, 2008).…”

A Novel Method for Screening G‐quadruplex Stabilizers to Human Telomeres

“…When in complex with telomere sequences, BMVC increases the melting temperature of G4 structure of telomere, 22,23 accelerates telomere length shortening, inhibits proliferation of cancer cells, and functions as a potential anticancer agent. 24 Recently, Neidle et al 20 found that the 3,6,9-trisubstituted acridine derivatives can significantly inhibit telomerase activity over 3,6-disubstituted derivatives. For example, a trisubstituted acridine compound, BRACO-19, is a well-known G4 stabilizer and telomerase inhibitor.…”