Phase I trial of combined therapy with bleomycin and the calmodulin antagonist, trifluoperazine

Hait, William N.; Morris, S.; Lazo, John S.; Figlin, R; Durivage, Henry J.; White, Kathleen Pogue; Schwartz, Peter E.

doi:10.1007/bf00435836

Cited by 31 publications

(10 citation statements)

References 22 publications

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“…Recent studies have shown that inositol phosphates serve as cofactors for DNA-PK cs during NHEJ (28 -30). Notably, inositol hexakisphosphate (InsP 6 ) has been shown to regulate the mobility of Ku proteins and depletion of InsP 6 by the TFP-related compound chlorpromazine causes a reduction in the mobile fraction of Ku (31). Therefore, one might speculate that the inhibitory action of TFP on DNA DSB repair shown in this study could be a consequence of calmodulin antagonism.…”

Section: Discussionmentioning

confidence: 77%

“…In addition, the phenothiazine compound trifluoperazine has been shown to enhance the cytotoxicity of the radiomimetic agent bleomycin (2 -5). Regimens that combine bleomycin and trifluoperazine (TFP) have also been evaluated in phase I and phase II clinical trials for the treatment of non -Hodgkin's lymphoma and glioblastoma multiforme, respectively (6,7). Although TFP clearly can modulate the cytotoxicity of several conventional chemotherapeutic agents, the molecular mechanisms underlying its antitumor activity remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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The antipsychotic drug trifluoperazine inhibits DNA repair and sensitizes non–small cell lung carcinoma cells to DNA double-strand break–induced cell death

Polischouk¹,

Holgersson²,

Zong³

et al. 2007

Molecular Cancer Therapeutics

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Trifluoperazine (TFP), a member of the phenothiazine class of antipsychotic drugs, has been shown to augment the cytotoxicity of the DNA-damaging agent bleomycin. In the present study, we investigated the effect of trifluoperazine on (a) survival of bleomycin-treated human non -small cell lung carcinoma U1810 cells, (b) induction and repair of bleomycin-induced DNA strand breaks, and (c) nonhomologous end-joining (NHEJ), the major DNA double-strand break (DSB) repair pathway in mammalian cells. By using a clonogenic survival assay, we show here that concomitant administration of trifluoperazine at a subtoxic concentration enhances the cytotoxicity of bleomycin. Moreover, trifluoperazine also increases the longevity of bleomycininduced DNA strand breaks in U1810 cells, as shown by both comet assay and fraction of activity released (FAR)-assay. This action seems to be related to suppression of cellular DNA DSB repair activities because NHEJmediated rejoining of DSBs occurs with significantly lower efficiency in the presence of trifluoperazine. We propose that TFP might be capable of inhibiting one or more elements of the DNA DSB repair machinery, thereby increasing the cytotoxicity of bleomycin in lung cancer cells. [Mol Cancer Ther 2007;6(8):2303 -9]

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Section: Discussionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

The antipsychotic drug trifluoperazine inhibits DNA repair and sensitizes non–small cell lung carcinoma cells to DNA double-strand break–induced cell death

Polischouk¹,

Holgersson²,

Zong³

et al. 2007

Molecular Cancer Therapeutics

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“…In conclusion, the enhancement of bleomycin cytotoxicity by anti-calmodulin drugs observed in preclinical models (5±9) and early clinical trials (10,11) appears to be due to the ability of the combination to induce apoptosis in susceptible cells.…”

Section: Discussionmentioning

confidence: 87%

“…Many calmodulin antagonists, such as trifluoperazine, have been shown to be cytotoxic to malignant cell lines (2–4). To study the potential of calmodulin anatagonists in combination with known anticancer drugs, we and others evaluated the interaction of anticlamodulin drugs with a variety of clinically useful agents, including bleomycin (5–10). These studies demonstrated that the addition of anticalmodulins, including phenothiazines, naphthalene sulfonamides, bee venom polypeptides, and diphenylbutylpiperidines, markedly increased the cytotoxicity of bleomycin to a variety of cell lines (5–10).…”

Section: Introductionmentioning

confidence: 99%

Augmentation of apoptosis by the combination of bleomycin with trifluoperazine in the presence of mutant p53

Sullivan¹,

Garcia-Welch²,

White

et al. 2002

J Exp Therapeutics

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A variety of anticalmodulin drugs can increase the cytotoxicity of bleomycin, a DNA damaging cancer chemotherapeutic. The combination has been shown to produce greater than expected DNA damage compared wot what was observed with either drug alone. Promising preclinical results led to Phase I and Phase II trials of trifluoperazine and bleomycin, which revealed activity in non-Hodgkin's lymphoma. Despite the unique activity of the combination, the mechanism underlying the DNA damaging effect remained poorly understood. In several systems, DNA damage leads to the induction of programmed cell death or apoptosis, which is characterized by interoligonucleosomal cleavage of DNA. To determine whether the activity of the combination of bleomycin with trifluoperazine was due to induction of apoptosis, we exposed L1210 leukemic lymphocytes to bleomycin in the presence or absence of trifluoperazine. The combination produced DNA laddering, cellular shrinkage, and chromatin condensation typical of programmed cell death. Cell cycle analyses revealed a blockade of cells in G2/M, suggesting the presence of mutant p53, which was confirmed by immunoanalysis. In addition, L1210 cells were found not to overexpress Bcl-2 in the presence or absence of drugs. These results indicate that the enhancement of bleomycin induced DNA damage by trifluoperazine is mediated, at least in part, through the induction of apoptosis.

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“…Although it needs to be confirmed by further in vivo toxicity analysis; several earlier reports have shown that phenothiazines are in general well-tolerated by cancer patients. 10, 15 To uncover responsible mechanisms for the preferential susceptibility of SCLC to phenothiazines, we dissected the molecular details of phenothiazine-induced cell death using multiple SCLC and NSCLC cell lines and with TFP as a model compound. We found that TFP treatment led to a rapid neutralization of lysosomal pH, as judged by decreased retention of the lysosomotropic dye LysoTracker Green, accompanied by accumulation of LC3-II in SCLC cells.…”

Section: Discussionmentioning

confidence: 99%

Harnessing the lysosome-dependent antitumor activity of phenothiazines in human small cell lung cancer

et al. 2014

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Phenothiazines are a family of heterocyclic compounds whose clinical utility includes treatment of psychiatric disorders as well as chemotherapy-induced emesis. Various studies have demonstrated that these compounds possess cytotoxic activities in tumor cell lines of different origin. However, there is considerable confusion regarding the molecular basis of phenothiazine-induced cell death. Lung cancer (LC) remains one of the most prevalent and deadly malignancies worldwide despite considerable efforts in the development of treatment strategies, especially new targeted therapies. In this work, we evaluated the potential utility of phenothiazines in human LC. We show that phenothiazines as single treatment decreased cell viability and induced cell death preferentially in small cell lung carcinoma (SCLC) over non small cell lung carcinoma (NSCLC) cell lines. Sensitivity to phenothiazines was not correlated with induction of apoptosis but due to phenothiazine-induced lysosomal dysfunction. Interestingly, the higher susceptibility of SCLC cells to phenothiazine-induced cell death correlated with an intrinsically lower buffer capacity in response to disruption of lysosomal homeostasis. Importantly, this effect in SCLC occurred despite mutation in p53 and was not influenced by intrinsic sensitivity/resistance toward conventional chemotherapeutic agents. Our data thus uncovered a novel context-dependent activity of phenothiazines in SCLC and suggest that phenothiazines could be considered as a treatment regimen of this disease, however, extended cell line analyses as well as in vivo studies are needed to make such conclusion.

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Phase I trial of combined therapy with bleomycin and the calmodulin antagonist, trifluoperazine

Cited by 31 publications

References 22 publications

The antipsychotic drug trifluoperazine inhibits DNA repair and sensitizes non–small cell lung carcinoma cells to DNA double-strand break–induced cell death

The antipsychotic drug trifluoperazine inhibits DNA repair and sensitizes non–small cell lung carcinoma cells to DNA double-strand break–induced cell death

Augmentation of apoptosis by the combination of bleomycin with trifluoperazine in the presence of mutant p53

Harnessing the lysosome-dependent antitumor activity of phenothiazines in human small cell lung cancer

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