Modulation of cis-diamminedichloroplatinum (II) accumulation and cytotoxicity by spermine in sensitive and resistant human ovarian carcinoma cells

Marverti, Gaetano; Andrews, Paul A.; Piccinini, Giulia; Ghiaroni, Stefania; Barbieri, Daniela; Moruzzi, Maria Stella

doi:10.1016/s0959-8049(96)00507-2

Cited by 39 publications

(38 citation statements)

References 19 publications

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“…As is evident from the Pt accumulation data, their modest cytotoxicity can be mainly explained by the scanty intracellular drug accumulation, that resulted quite limited when compared with other Pt-containing drugs, such as cDDP [28,29].…”

Section: Discussionmentioning

confidence: 99%

“…After three days, incubations were terminated by washing four times with ice-cold PBS and cells were scraped into 0.1% Triton-X-100 in 0.1 M HCl and frozen until use. After thawing and sonication, cell-associated Pt was measured with a Perkin-Elmer Model AAnalyst 600 (Perkin-Elmer, Norwalk, CT) atomic absorption spectrophotometer equipped with a graphite furnace accessory, as previously described [29]. Each sample was run in duplicate.…”

Section: Bipyridyl-pt(ii)-thiourea Complexes Intracellular Accumulationmentioning

confidence: 99%

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Studies on the anti-proliferative effects of novel DNA-intercalating bipyridyl–thiourea–Pt(II) complexes against cisplatin-sensitive and -resistant human ovarian cancer cells

Marverti

Cusumano

Ligabue

et al. 2008

Journal of Inorganic Biochemistry

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Section: Discussionmentioning

confidence: 99%

Section: Bipyridyl-pt(ii)-thiourea Complexes Intracellular Accumulationmentioning

confidence: 99%

Studies on the anti-proliferative effects of novel DNA-intercalating bipyridyl–thiourea–Pt(II) complexes against cisplatin-sensitive and -resistant human ovarian cancer cells

Marverti

Cusumano

Ligabue

et al. 2008

Journal of Inorganic Biochemistry

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“…[46] Tested on the 2008/C13* cell pair, the resistance factor of 24 was about 17-fold lower than that of cisplatin, clearly revealing no cross-resistance phenomena. Acquired MDR, whereby cells become refractory to multiple drugs, poses a most important challenge to the success of anticancer chemotherapy.…”

Section: Antiproliferative Activitymentioning

confidence: 93%

DNA Binding Ellipticine Analogues: Synthesis, Biological Evaluation, and Structure–Activity Relationships

et al. 2009

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In connection with our interest in the synthesis and study of the biological properties of ellipticine analogues as anticancer agents, some 7H-pyrido[2,3-c]carbazoles (7H-PyC) and their corresponding tetrahydro derivatives (7H-THPyC) were synthesized. A common multistep pathway characterized by conventional reactions involving carbazole Fischer and Conrad-Limpach quinoline syntheses yielded the tetracyclic compounds. With the aim to improve the cytotoxic activity of the new 7H-PyC derivatives, we provided them with one or two diethylaminoethyl side chains. The new THPyCs, PyCs, and smaller pyrroloquinoline (PQ) derivatives were tested for their in vitro cytotoxic properties against several human tumor cell lines. Most of the compounds tested showed considerable cytotoxic activity, particularly compound 24, which, with two basic alkylamino chains, has IC(50) values in the sub-micromolar range, about one order of magnitude lower than those of the reference compound, ellipticine. Chemosensitivity tests on cisplatin-, mitoxantrone-, and multidrug-resistant (MDR) phenotypes indicated that compound 24 shows no cross-resistance; this suggests that, besides not being a potential MDR substrate, it might act as a mixed inhibitor of topoisomerases I and II. Flow cytometric and caspase-3 activation analyses revealed that 24 induces a caspase-3-dependent apoptotic cell-death mechanism. Linear dichroism and unwinding experiments suggested that the most active compounds act as DNA intercalators. For compound 24, an inhibitory concentration-dependent effect on topoisomerases II and I was demonstrated. Herein we discuss interesting structure-activity relationships with respect to molecular size and planarity, as well as the substitution and position of one side chain on the PyC nucleus, in comparison with corresponding smaller PQs.

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“…Membrane permeability studies were carried out on subconfluent cells seeded into 6-well plates and treated, after medium aspiration, with 1 ml RPMI 1640 medium containing 1 mM [ 3 H]mannitol (1 μCi/ml) (Sigma) [22] with or without drug F in the same conditions as described for cytotoxicity, the permeability marker being added for the final hour of incubation. Then, the medium was aspirated and the wells rapidly washed four times with ice-cold PBS.…”

Section: Membrane Permeability By [ 3 H] Mannitol Accumulationmentioning

confidence: 99%

Characterization of the cell growth inhibitory effects of a novel DNA-intercalating bipyridyl-thiourea-Pt(II) complex in cisplatin-sensitive and—resistant human ovarian cancer cells

et al. 2009

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The cellular effects of a novel DNA-intercalating agent, the bipyridyl complex of platinum(II) with diphenyl thiourea, [Pt(bipy)(Ph(2)-tu)(2)]Cl(2), has been analyzed in the cisplatin (cDDP)-sensitive human ovarian carcinoma cell line, 2008, and its -resistant variant, C13* cells, in which the highest accumulation and cytotoxicity was found among six related bipyridyl thiourea complexes. We also show here that this complex causes reactive oxygen species to form and inhibits topoisomerase II activity to a greater extent in the sensitive than in the resistant line. The impairment of this enzyme led to DNA damage, as shown by the comet assay. As a consequence, cell cycle distribution has also been greatly perturbed in both lines. Morphological analysis revealed deep cellular derangement with the presence of cellular masses, together with increased membrane permeability and depolarization of the mitochondrial membrane. Some of these effects, sometimes differentially evident between the two cell lines, might also be related to the decrease of total cell magnesium content caused by this thiourea complex both in sensitive and resistant cells, though the basal content of this ion was higher in the cDDP-resistant line. Altogether these results suggest that this compound exerts its cytotoxicity by mechanisms partly mediated by the resistance phenotype. In particular, cDDP-sensitive cells were affected mostly by impairing topoisomerase II activity and by increasing membrane permeability and the formation of reactive oxygen species; conversely, mitochondrial impairment appeared to play the most important role in the action of complex F in resistant cells.

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Modulation of cis-diamminedichloroplatinum (II) accumulation and cytotoxicity by spermine in sensitive and resistant human ovarian carcinoma cells

Cited by 39 publications

References 19 publications

Studies on the anti-proliferative effects of novel DNA-intercalating bipyridyl–thiourea–Pt(II) complexes against cisplatin-sensitive and -resistant human ovarian cancer cells

Studies on the anti-proliferative effects of novel DNA-intercalating bipyridyl–thiourea–Pt(II) complexes against cisplatin-sensitive and -resistant human ovarian cancer cells

DNA Binding Ellipticine Analogues: Synthesis, Biological Evaluation, and Structure–Activity Relationships

Characterization of the cell growth inhibitory effects of a novel DNA-intercalating bipyridyl-thiourea-Pt(II) complex in cisplatin-sensitive and—resistant human ovarian cancer cells

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