Substituted titanocenes induce caspase-dependent apoptosis in human epidermoid carcinoma cells in vitro and exhibit antitumour activity in vivo

Bannon, John H.; Fichtner, Iduna; O'Neill, Alison; Pampillón, Clara; Sweeney, Nigel J.; Strohfeldt, Katja; Watson, R. William G.; Tacke, Matthias; Gee, Margaret M. Mc

doi:10.1038/sj.bjc.6604021

Cited by 50 publications

(37 citation statements)

References 33 publications

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“…Since the precise mechanism underlying the observed changes in hTerT promoter activity in cancer cells is unclear, detailed investigations are needed. Here, cell cycle arrest at the S phase was demonstrated in Hela cells in response to cisplatin, in accordance with the results of other studies (22,23). it is known that telomerase synthesizes telomeres during the S phase, and that telomerase activity markedly increases during this phase of the cell cycle (24).…”

Section: Fold Induction Ddp (µG/ml)supporting

confidence: 79%

Enhanced suicide gene therapy using a tumor-specific promoter in combination with cisplatin

Zhou¹

2009

Mol Med Rep

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Abstract. Human telomerase reverse transcriptase (hTerT) promoter has been proposed in cancer-targeted gene therapy. However, this promoter has not been strong enough to achieve therapeutic levels of transgene expression. We favor the hypothesis that telomerase may participate in the process of dna repair and that the up-regulation of hTerT promoter activity may be a reaction to dna damage. in previous investigations, we tested an ῾indirected-activator' strategy that utilizes radiation to increase the activity of the hTerT promoter. The purpose of the present study was to implement a strategy using cisplatin to enhance hTerT promoter activity. The results indicate that, in human uterine cervical cancer (HeLa) cells exposed to 5 µg/ml cisplatin, the hTerT promoter had 3.1-fold increased activity compared to untreated cells. in addition, the combination of cisplatin and hTerT promoter-mediated horseradish peroxidase/indole-3 -acetic acid gene-directed enzyme prodrug therapy induced cell cycle arrest at the S phase and apoptosis leading to a more significant reduction in cell viability. These findings suggest that hTerT promoter-mediated gene therapy is improved when combined with cisplatin. IntroductionSelective gene therapy, which utilizes a tumor-specific promoter to control the transgene, represents a potent strategy in cancer treatment. Telomerase is a ribonucleoprotein complex that is activated in approximately 90% of cancers, but not in most normal cells (1). Human telomerase reverse transcriptase (hTerT) is the catalytic subunit of telomerase, and determines telomerase activity (2). Thus, the hTerT promoter has been widely used in gene therapy targeting cancer cells (3,4). However, the activity of the promoter may not be strong enough to induce the expression of a significant amount of the therapeutic gene product required to kill cancer cells (5,6).radiotherapy is one of the major clinical treatment options for malignant tumors; however, cellular dna damage responses are triggered when cells are exposed to irradiation. data from our previous investigations suggested that telomerase plays a role in healing radiation-induced dna damage (7). We also observed that radiation can be used to increase the activity of the hTERT promoter (8). Cisplatin is one of the most efficient chemotherapeutic agents in use, exerting its cytotoxic effect through the formation of intra-strand and inter-strand Pt-dna cross-links. We favor the hypothesis that telomerase may participate in the process of dna repair, and that the up-regulation of hTerT promoter activity may be a reaction to dna damage. Thus, cisplatin may be used to enhance hTerT promoter activity. This is promising in cancer-targeted gene therapy.The aim of the present study was to determine the potential of utilizing cisplatin to enhance hTerT promoter activity. The human uterine cervical cancer cell line Hela was used, since the hTerT promoter has been applied to mediate tumorspecific expression in cervical cancer cells (9,10). Cisplatin is the standard systemic c...

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Section: Fold Induction Ddp (µG/ml)supporting

confidence: 79%

Enhanced suicide gene therapy using a tumor-specific promoter in combination with cisplatin

Zhou¹

2009

Mol Med Rep

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“…Bannon et al demonstrated cell cycle perturbation and late apoptotic A431 epidermoid carcinoma cell populations following exposure to cisplatin or titanocene Y (3; 50 µM; 48 h) 24 , indicative of caspase-induced apototosis. Similarly, gene expression analysis in small cell lung cancer cells treated with related species was in accord with DNA damage being the apoptosis trigger 25 .…”

Section: Cell Cycle Analyses γH2ax Foci and Apoptosismentioning

confidence: 99%

Enantiopure titanocene complexes – direct evidence for paraptosis in cancer cells

et al. 2016

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“…Since titanocene C exhibits a pattern of cytotoxicity different from cisplatin in a panel of cell lines, it is expected to constitute an interesting novel compound for treatment of SCLC which warrants further development. Finally, it should be mentioned that significant antitumor activity has been already reported for the class of titanocene compounds in experimental animal xenograft models [3,31].…”

Section: Discussionmentioning

confidence: 97%

Anticancer activity and mode of action of titanocene C

et al. 2010

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Titanocenes constitute a class of metal-based anticancer agents that seem to display a mode of action distinct from that of platinum complexes and to be more tolerable with a differing spectrum of activity. In the present study, titanocene C (bis-(N,N-dimethylamino-2(N-methylpyrrolyl)-methyl-cyclopentadienyl) titanium(IV) dichloride) was shown to exhibit antiproliferative activity against human tumor cell lines with a mean IC₅₀ value of 48.3 ± 32.5 µM. In particular, high activity was found against small cell lung cancer (SCLC) cell lines with a profile different from cisplatin. Titanocene C induced cell cycle arrest at the G1/0-S interphase. Cross-resistance to either cisplatin or oxoplatin, respectively, was low for titanocene C and absent for titanocene Y in variant HL-60 cell lines. Alterations in gene expression of NCI-H526 SCLC cells induced by titanocene C were investigated using genome-wide expression arrays. Downregulation was found for genes coding for topoisomerases I and IIα, histones of the HIST1H4 cluster, enzymes involved in glycolysis, components of the cytoskeleton and vesicular transport, among others. In contrast, expression of genes involved in apoptosis, stress response, particularly members of the metallothionein gene cluster 1, DNA damage and growth factors was upregulated following exposure to titanocene C. Approximately 50% of those genes downregulated by titanocene C and cisplatin were concordant, including the previously identified markers of cisplatin-sensitivity, tubulin and stathmin, indicating partial overlap of the pathways affected by these metal complexes. The present findings point helicases/topoisomerases and HIST1H4 core histones out as targets of titanocene C and metallothioneins as putative main effectors of drug resistance.

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Substituted titanocenes induce caspase-dependent apoptosis in human epidermoid carcinoma cells in vitro and exhibit antitumour activity in vivo

Cited by 50 publications

References 33 publications

Enhanced suicide gene therapy using a tumor-specific promoter in combination with cisplatin

Enhanced suicide gene therapy using a tumor-specific promoter in combination with cisplatin

Enantiopure titanocene complexes – direct evidence for paraptosis in cancer cells

Anticancer activity and mode of action of titanocene C

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