Flunarizine enhancement of melphalan activity against drug-sensitive/resistant rhabdomyosarcoma

Castellino, Sharon M.; Friedman, Henry S.; Elion, Gertrude B.; Ong, E. T.; Marcelli, Susan; Page, Rodney L.; Bigner, Darell D.; Dewhirst, Mark W.

doi:10.1038/bjc.1995.230

Cited by 12 publications

(8 citation statements)

References 23 publications

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“…Our top scoring ligands screened through our virtual screening protocol included previously reported potent ABCB1 and ABCG2 inhibitors imatinib 28 and a weak inhibitor NVP-BHG712 29 . flunarizine 30 , and ABCB1 substrate baicalin 31 . These results indicated great potential and validity of our screening protocol.…”

Section: Discussionmentioning

confidence: 99%

Bafetinib (INNO-406) reverses multidrug resistance by inhibiting the efflux function of ABCB1 and ABCG2 transporters

Zhang

Wang

et al. 2016

Sci Rep

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ATP-Binding Cassette transporters are involved in the efflux of xenobiotic compounds and are responsible for decreasing drug accumulation in multidrug resistant (MDR) cells. Discovered by structure-based virtual screening algorithms, bafetinib, a Bcr-Abl/Lyn tyrosine kinase inhibitor, was found to have inhibitory effects on both ABCB1- and ABCG2-mediated MDR in this in-vitro investigation. Bafetinib significantly sensitized ABCB1 and ABCG2 overexpressing MDR cells to their anticancer substrates and increased the intracellular accumulation of anticancer drugs, particularly doxorubicin and [3H]-paclitaxel in ABCB1 overexpressing cells; mitoxantrone and [3H]-mitoxantrone in ABCG2 overexpressing cells, respectively. Bafetinib stimulated ABCB1 ATPase activities while inhibited ABCG2 ATPase activities. There were no significant changes in the expression level or the subcellular distribution of ABCB1 and ABCG2 in the cells exposed to 3 μM of bafetinib. Overall, our study indicated that bafetinib reversed ABCB1- and ABCG2-mediated MDR by blocking the drug efflux function of these transporters. These findings might be useful in developing combination therapy for MDR cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Bafetinib (INNO-406) reverses multidrug resistance by inhibiting the efflux function of ABCB1 and ABCG2 transporters

Zhang

Wang

et al. 2016

Sci Rep

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“…Albumin protects neuroblastoma cells from flunarizine-induced cytotoxicity by preventing mitochondrial depolarization and, presumably, the subsequent activation of the caspase cascade. Flunarizine also sensitizes leukemia cells to vincristineinduced cell death [11] and ovarian carcinoma cells and rhabdomyosarcoma cells to melphalan-induced cytotoxicity [12,13].…”

Section: Introductionmentioning

confidence: 99%

The Ca2+ channel blocker flunarizine induces caspase-10-dependent apoptosis in Jurkat T-leukemia cells

Conrad¹,

Furlong²,

Doucette³

et al. 2010

Apoptosis

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Flunarizine is a Ca(2+) channel blocker that can be either cytoprotective or cytotoxic, depending on the cell type that is being examined. We show here that flunarizine was cytotoxic for Jurkat T-leukemia cells, as well as for other hematological maligancies, but not for breast or colon carcinoma cells. Treatment of Jurkat cells with flunarizine resulted in caspase-3 activation, poly (ADP-ribose) polymerase cleavage, and laddering of DNA fragments, all of which are hallmarks of apoptosis. Flunarizine-induced DNA fragmentation was inhibited by the caspase-3 inhibitor z-DEVD-fmk, the caspase-8/caspase-10 inhibitor z-IETD-fmk, and the caspase-10 inhibitor z-AEVD-fmk, but was not reduced in caspase-8-deficient Jurkat cells, indicating the involvement of caspase-10 upstream of caspase-3 activation. Interestingly, FADD recruitment to a death receptor was not involved since flunarizine caused DNA fragmentation in FADD-deficient Jurkat cells. Flunarizine treatment of Jurkat cells also resulted in reactive oxygen species production, dissipation of mitochondrial transmembrane potential, release of cytochrome c from mitochondria, and caspase-9 activation, although none of these events were necessary for apoptosis induction. Collectively, these findings indicate that flunarizine triggers apoptosis in Jurkat cells via FADD-independent activation of caspase-10. Flunarizine warrants further investigation as a potential anti-cancer agent for the treatment of hematological malignancies.

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“…Horsman et al (1996) have shown that tumour blood flow changes brought about by nitro-L-arginine lasted no more than an hour, whereas the changes in redox status reported by Wood et al (1994a) could last for up to 6 h. Thus, the underlying mechanism mediating these anti-tumour effects is likely to be a complex interaction between hypoxia induction and entrapment (distribution and pharmacokinetics). Such interactions have been shown to contribute to the potentiation of the activity of both RSU1069 and the alkylating agent melphalan using a variety of techniques for modifying blood flow to tumours (Chaplin and Acker 1987;Stratford et al, 1988;Bremner et al, 1990;Castellino et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Enhancement of bioreductive drug toxicity in murine tumours by inhibition of the activity of nitric oxide synthase

Butler

Wood²,

Cole³

et al. 1997

Br J Cancer

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Summary Nitro-L-arginine inhibits the production of nitric oxide and can thereby cause vasoconstriction in vivo. One consequence of this is that nitro-L-arginine can increase hypoxia in a range of transplantable and spontaneous murine solid tumours. Bioreductive drugs such as RB6145 are more active under hypoxic conditions, and the combination of RB6145 with nitro-L-arginine in vivo shows greater anti-tumour activity than either agent individually. In mice given nitro-L-arginine at 10 mg kg-' i.p. up to 1 h before or after 300 mg kg-' i.p. RB6145, survival of KHT tumour cells was reduced by 3-4 logs when assessed by clonogenic assay 24 h after treatment. RB6145 or nitro-L-arginine alone caused no more than 20% cell kill. Similar effects were found in SCCVII tumours. The tumour response to the drug combination was tumour size dependent, with increased tumour cell sensitivity occurring when the tumour volume at the time of treatment was increased. Further, the response of KHT tumours to the combination of RB6145 and nitro-L-arginine was also dependent on the time interval between treatment and on when tumours were excised for determination of survival in vitro. The relative surviving fraction was about 0.3 for intervals less than 4 h but was reduced to 0.01 at 12 h and 0.001 at 24 h. These results were supported by histological examination of tumours, when necrosis at 2 h after treatment was less than 5% but increased to greater than 90% at 24 h. RB6145-induced normal tissue damage, as measured by CFU-A survival, was not altered by combining with nitro-L-arginine. Hence, this drug combination may provide therapeutic benefit. It is likely that the substantial anti-tumour effects are due to enhancement of bioreductive toxicity through increased tumour hypoxia, although additional mechanism(s) may also contribute to the overall response.

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Flunarizine enhancement of melphalan activity against drug-sensitive/resistant rhabdomyosarcoma

Cited by 12 publications

References 23 publications

Bafetinib (INNO-406) reverses multidrug resistance by inhibiting the efflux function of ABCB1 and ABCG2 transporters

Bafetinib (INNO-406) reverses multidrug resistance by inhibiting the efflux function of ABCB1 and ABCG2 transporters

The Ca2+ channel blocker flunarizine induces caspase-10-dependent apoptosis in Jurkat T-leukemia cells

Enhancement of bioreductive drug toxicity in murine tumours by inhibition of the activity of nitric oxide synthase

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