Neutral Metoclopramide Induces Tumor Cytotoxicity and Sensitizes Ionizing Radiation of a Human Lung Adenocarcinoma and Virus Induced Sarcoma in Mice

Olsson, Åsa; Hua, Jianyi; Sheng, Yuchen; Pero, Ronald W.

doi:10.3109/02841869709001271

Cited by 10 publications

(7 citation statements)

References 28 publications

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“…NF-B activation can also protect cells from oxidative injury (Chen and Cedarbaum, 1997) and induce the transcriptional activation of multiple genes that suppress apoptosis (Baldwin, 2001). The inhibition of NF-B is one plausible basis for the observed radiosensitization and cytotoxicity induced by metoclopramide in tumor cells (Olsson et al, 1997;.…”

Section: Discussionmentioning

confidence: 99%

N-Substituted 4-Aminobenzamides (Procainamide Analogs): An Assessment of Multiple Cellular Effects Concerning Ion Trapping

Morissette¹,

Moreau²,

C.‐Gaudreault³

et al. 2005

Molecular Pharmacology

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Procainamide and related triethylamine-substituted 4-aminobenzamides, such as metoclopramide and declopramide, exert cellular effects potentially exploitable in oncology at millimolar concentrations (DNA demethylation, nuclear factor-B inhibition, apoptosis) and display anti-inflammatory properties. However, these drugs induce massive cell vacuolization at similar concentrations, a response initiated by vacuolar (V-) ATPasedependent ion trapping into and osmotic swelling of acidic organelles. We have examined whether this overlooked response might be related to the effects on cell proliferation and viability using cultured vascular smooth muscle cells and tumor-derived cell lines (Morris 7777 hepatoma, HT-1080 fibrosarcoma). Giant vacuole formation, of confirmed trans-Golgi origin (labeled with C5-ceramide, p230, golgin-97), is a cellular response to all tested amines in the series (Ն2.5 mM), including triethylamine. These drugs and the V-ATPase inhibitor bafilomycin A1 inhibited smooth muscle cell proliferation, suggesting that acidification of a cellular compartment is essential to cell division. The cytotoxicity was maximal with metoclopramide, and this effect was minimally influenced by bafilomycin A1; furthermore, metoclopramide (2.5 mM) induced apoptosis in tumor cells as judged by poly(ADP-ribose)polymerase (PARP) cleavage. Triethylamine and procainamide exhibit a low level of cytotoxicity variably reduced by bafilomycin cotreatment. In Morris cells, the secretion of ␣-fetoprotein is inhibited by amines, consistent with the impairment of the secretory pathway. The most highly substituted 4-aminobenzamides are significant NF-B inhibitors in smooth muscle cells. Although some effects of 4-aminobenzamides are independent of VATPase-driven ion trapping (inhibition of NF-B nuclear translocation, agent-specific cytotoxicity, PARP cleavage), other effects are dependent on this phenomenon (vacuolization, a component of the cytotoxicity, inhibition of secretion).We have recently addressed the mechanism of the massive cell vacuolization induced by many organic amines at millimolar concentrations; procainamide, an N-substituted 4-aminobenzamide, was the prototype drug used in most assays (Morissette et al., 2004a), but the effect was shared by structurally simpler tertiary amines, such as triethylamine (Fig.

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Section: Discussionmentioning

confidence: 99%

N-Substituted 4-Aminobenzamides (Procainamide Analogs): An Assessment of Multiple Cellular Effects Concerning Ion Trapping

Morissette¹,

Moreau²,

C.‐Gaudreault³

et al. 2005

Molecular Pharmacology

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“…The N-substituted benzamides have been shown to have multiple modes of biological activity, because they: (i) have D 2 -and 5-HT 3 -receptor binding affinity (Harrington et al, 1983); (ii) induce apoptosis and inhibit proliferation in vitro (Pero et al, 1998;Liberg et al, 1999); (iii) sensitise low dose radiation and delay in vivo tumour growth Olsson et al, 1997); (iv) have anti-inflammatory properties by inhibiting NFkB activity in human Jurkat T-cells (Lindgren et al, 2001) and mouse pre-B 70Z/3 cells (Liberg et al, 1999) and finally; (v) inhibit TNFa production in vitro as well as in vivo . To eliminate species specific responses we have utilised two different haematopoetic cell lines, 70Z/3 mouse pre-B-cells and human HL60 promyelocytic leukaemia cells, to study the mechanism of apoptosis induced by N-substituted benzamides.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, MCA and 3CPA have earlier been shown to have radio-and chemo-sensitising properties in vivo in murine and human tumour models (Kjellen et al, 1989(Kjellen et al, , 1995Olsson et al, 1997). 3CPA in combination with 5-FU (5-flourouracil) or cisplatin has recently completed phase-1 studies in patients with advanced stage cancers.…”

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confidence: 99%

Mechanism of action for N-substituted benzamide-induced apoptosis

et al. 2002

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We have analysed the mechanism of action for induction of apoptosis by N-substituted benzamides using declopramide as a lead compound. We show here that declopramide at doses above 250 mM in the mouse 70Z/3 pre-B cell line or in the human promyeolocytic cancer cell line HL60 induced cytochrome c release into the cytosol and caspase-9 activation. The broad spectrum caspase inhibitor zVADfmk and caspase-9 inhibitor zLEDHfmk inhibited apoptosis and improved cell viability when administrated to cells 1 h before exposure to declopramide, whereas the caspase-8 inhibitor zIEDHfmk had less effect. Also, the over expression of Bcl-2 by transfection in 70Z/3 cells inhibited declopramide-induced apoptosis. Prior to the induction of apoptosis, a G 2 /M cell cycle block was induced by declopramide. The cell cycle block was also observed in the presence of broad spectrum caspase inhibitor zVADfmk and in a transfectant expressing high levels of Bcl-2. Furthermore, while p53 was induced in 70Z/3 cells by declopramide, neither the apoptotic mechanism nor the G 2 /M cell cycle block were dependent on p53 activation since both effects were also seen in p53 deficient HL60 cells after addition of declopramide.

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“…Some of these molecules, e.g. declopramide (3-CPA) and metoclopramide (MCA) have previously been studied in vitro, in vivo and in clinical models (Kjellen et al, 1989(Kjellen et al, , 1995Lybak et al, 1990;Lybak and Pero, 1991;Hua et al, 1995Werning et al, 1995;Olsson et al, 1997;Pero et al, 1998), and have been shown to be biologically active.…”

Section: Rapid Induction Of Apoptosis By N-substituted Benzamidesmentioning

confidence: 99%

N-substituted benzamides inhibit NFκB activation and induce apoptosis by separate mechanisms

et al. 1999

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Benzamides have been in clinical use for many years in treatment against various disorders. A recent application is that as a sensitizer for radio- or chemotherapies. We have here analysed the mechanism of action of N-substituted benzamides using an in vitro system. We found that while procainamide was biologically inert in our system, the addition of a chloride in the 3′ position of the benzamide ring created a compound (declopramide) that induced rapid apoptosis. Furthermore, declopramide also inhibited NFκB activation by inhibition of IκBβ breakdown. An acetylated variant of declopramide, N-acetyl declopramide, showed no effect with regard to rapid apoptosis induction but was a potent inhibitor of NFκB activation. In fact, the addition of an acetyl group to procainamide in the 4′ position was sufficient to convert this biologically inactive substance to a potent inhibitor of NFκB activation. These findings suggest two potential mechanisms, induction of early apoptosis and inhibition of NFκB mediated salvage from apoptosis, for the biological effect of N-substituted benzamides as radio- and chemo-sensitizers. In addition it suggests that N-substituted benzamides are potential candidates for the development of anti-inflammatory compounds using NFκB as a drug target. © 1999 Cancer Research Campaign

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Neutral Metoclopramide Induces Tumor Cytotoxicity and Sensitizes Ionizing Radiation of a Human Lung Adenocarcinoma and Virus Induced Sarcoma in Mice

Cited by 10 publications

References 28 publications

N-Substituted 4-Aminobenzamides (Procainamide Analogs): An Assessment of Multiple Cellular Effects Concerning Ion Trapping

N-Substituted 4-Aminobenzamides (Procainamide Analogs): An Assessment of Multiple Cellular Effects Concerning Ion Trapping

Mechanism of action for N-substituted benzamide-induced apoptosis

N-substituted benzamides inhibit NFκB activation and induce apoptosis by separate mechanisms

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