| Reference | 1. Mol Pharmacol. 2005 Dec;68(6):1551-8. Epub 2005 Sep 8.
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Pharmacodynamics of the G-quadruplex-stabilizing telomerase inhibitor
3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4)
in vitro: activity in human tumor cells correlates with telomere length and can
be enhanced, or antagonized, with cytotoxic agents.
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Cookson JC(1), Dai F, Smith V, Heald RA, Laughton CA, Stevens MF, Burger AM.
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Author information: <br>
(1)Centre for Biomolecular Sciences, School of Pharmacy, University of
Nottingham, Nottingham NG7 2RD, United Kingdom.
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Telomeric integrity is required to maintain the replicative ability of cancer
cells and is a target for the G-quadruplex-stabilizing drug
3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4).
We report a senescent-like growth arrest in MCF-7 breast cancer cells, within 14
to 17 days, and a reduction in telomere length (from 5.2 kilobases (kb) to 4.7
and 4.3 kb after 17 days of treatment at 0.5 and 1 microM, respectively). These
effects occurred at noncytotoxic drug concentrations (doses < 1 microM over a
14-day exposure) compatible with long-term drug dosing. The telomere length of
cancer cells influences their sensitivity to growth inhibition by RHPS4: mutant
(mt) human telomerase reverse transcriptase (hTERT)-expressing MCF-7 cells [short
telomere restriction fragment (TRF) length, 1.9 kb; IC50, 0.2 microM] were 10
times more sensitive to RHPS4 compared with wild-type (wt) hTERT-expressing,
vector-transfected control cells (longer TRF-length 5.2 kb; IC50 2 microM) in the
5 day SRB assay. This relationship was corroborated in a panel of 36 human tumor
xenografts grown in vitro showing a positive correlation between telomere length
and growth inhibitory potency of RHPS4 (15-day clonogenic assay, r = 0.75). These
observations are consistent with loss of the protective capping status of
telomeres mediated by RHPS4 G-quadruplex-stabilization, thus leading to greater
susceptibility of cells with shorter telomeres. In combination studies,
paclitaxel (Taxol), doxorubicin (Adriamycin), and the experimental therapeutic
agent 17-(allylamino)-17-demethoxygeldanamycin, which inhibits the 90-kDa heat
shock protein, conferred enhanced sensitivity in RHPS4 treated MCF-7 cells,
whereas the DNA-interactive temozolomide and cisplatin antagonized the action of
RHPS4. Our results support the combined use of certain classes of cytotoxic
anticancer agents with RHPS4 to enhance potential clinical benefit.
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2. Mol Pharmacol. 2004 Nov;66(5):1138-46. Epub 2004 Aug 10.
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Biological activity of the G-quadruplex ligand RHPS4
(3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate) is
associated with telomere capping alteration.
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Leonetti C(1), Amodei S, D/’Angelo C, Rizzo A, Benassi B, Antonelli A, Elli R,
Stevens MF, D/’Incalci M, Zupi G, Biroccio A.
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Author information: <br>
(1)Experimental Chemotherapy Laboratory, Centro di Ricerca Sperimentale, Regina
Elena Cancer Institute, University La Sapienza, Roma, Italy.
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This study had two goals: 1) to evaluate the biological effect of the novel
pentacyclic acridine 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium
methosulfate (RHPS4) on human melanoma lines possessing long telomeres, and 2) to
elucidate the relationship between G-quadruplex-based telomerase
inhibitor-induced cellular effects and telomere length/dysfunction. The cellular
pharmacological effects of RHPS4 have been evaluated by treating melanoma lines
with increasing concentrations of RHPS4. A dose-dependent inhibition of cell
proliferation was observed in all the lines during short-term treatment. Flow
cytometric analysis demonstrated that RHPS4 induced a dose-dependent accumulation
of cells in the S-G(2)/M phase of cell cycle. The RHPS4-induced cell cycle
alteration was irreversible even at low doses, and the cells died from apoptosis.
At high RHPS4 concentration, apoptosis was accompanied by the induction of a
senescence phenotype: large cell size, vacuolated cytoplasm, and
beta-galactosidase activity. The short-term biological activity of RHPS4 was not
caused by telomere shortening, but it was associated with telomere dysfunction,
in terms of presence of telomeric fusions, polynucleated cells, and typical
images of telophase bridge. In conclusion, our results demonstrate that the
G-quadruplex ligand RHPS4 can function in a telomere length-independent manner
through its ability to cause telomere-capping alteration.
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