BubR1 Is Required for a Sustained Mitotic Spindle Checkpoint Arrest in Human Cancer Cells Treated with Tubulin-Targeting Pyrrolo-1,5-Benzoxazepines

Greene, Lisa M.; Campiani, Giuseppe; Lawler, Mark; Williams, David C.; Zisterer, Daniela M.

doi:10.1124/mol.107.039024

Cited by 39 publications

(57 citation statements)

References 31 publications

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“…17,18 Among these compounds, PBOX-6 was previously tested in CRC models using a murine colon carcinoma cell line (CT-26) and Caco-2, a human colon carcinoma derived cell line able to differentiate in culture. 28 In our work, during a screening program, we identified a compound belonging to the family of pyrrole-1,5-benzoxazepine, PBOX-15, as a submicromolar selective inhibitor of FAAH enzyme in rat brain membranes (IC50 D 0.843 mM).…”

Section: Discussionmentioning

confidence: 99%

“…18 Wild-type HeLa cells suggests that FAAH activity is not an absolute requirement for cell growth control and, as a consequence, the anti-proliferative effects could be ascribed, only in part, to FAAH inhibition. However, the obtained results demonstrate that PBOX-15 is able to significantly modulate cellular pathways involved in the proliferation and progression of CRC.…”

Section: Discussionmentioning

confidence: 99%

“…16 In particular, PBOX-15 is a tubulin depolymerizing agent displaying a proapoptotic activity in a variety of human solid and hematological malignancies, [16][17][18][19][20][21] with minimal toxicity toward normal blood and bone marrow cells. 17 In the present study we identified PBOX-15 as a submicromolar selective inhibitor of FAAH enzyme (IC50= 0.843 mM) and we investigated the anti-tumor efficacy and mode of action of this compound on CRC cell lines.…”

Section: Introductionmentioning

confidence: 99%

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Antitumor effect of pyrrolo-1,5-benzoxazepine-15 and its synergistic effect with Oxaliplatin and 5-FU in colorectal cancer cells

Fiore

Proto

Pisanti

et al. 2015

Cancer Biology & Therapy

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Some compounds of a series of novel pyrrolo-1,5-benzoxa(thia)zepine, a well-known group of tubulin targeting agents, display anti-tumor effects mainly inducing cell cycle arrest and apoptosis in several human cancer models. A member of this family, pyrrolo-1,5-benzoxazepine-15 (PBOX-15), has previously shown potent pro-apoptotic activity in a variety of human tumor cell types, with minimal toxicity toward normal blood and bone marrow cells. In this study, we evaluated the PBOX-15-mediated effects in human colorectal cancer cell (CRC) lines, DLD-1 and HT-29. The compound, used at concentrations equal to or greater than 1 mM, inhibited the proliferation of human CRC cells, inducing a significant cell cycle arrest in the G2/M phase. In DLD-1 cells, treatments prolonged over 48 h triggered a strong activation of the intrinsic apoptotic pathway as indicated by activation of caspase-9, caspase-3 and PARP cleavage. Moreover, nanomolar concentrations of PBOX-15, significantly improved the oxaliplatin and 5-fluouracilinduced anti-proliferative effects in DLD1 cell line. The observed synergistic interaction of both PBOX-15/ Oxaliplatin and PBOX-15/5FU may involve activation of p38 MAPK and JNK pathway, which in turn significantly increased caspase-3 cleavage in DLD-1 cells, treated with PBOX-5/Oxaliplatin but not with PBOX-15/5FU. Moreover, PBOX-15/5FU-treated cells showed an increase in expression of the proapoptotic protein Bax. Taken together, these results show that PBOX-15 could represent a promising compound for the treatment of human CRC and a strong candidate for novel therapeutic options.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Antitumor effect of pyrrolo-1,5-benzoxazepine-15 and its synergistic effect with Oxaliplatin and 5-FU in colorectal cancer cells

Fiore

Proto

Pisanti

et al. 2015

Cancer Biology & Therapy

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“…We have also elucidated that in response to PBOX-treatment, some cell types, such as K562 cells, exhibited a sustained mitotic arrest while other cell types, such as HL60 cells, arrested transiently and then proceeded to undergo apoptosis (16).…”

Section: Introductionmentioning

confidence: 94%

Dual targeting of tumour cells and host endothelial cells by novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines

Nathwani

Butler

Meegan

et al. 2009

Cancer Chemother Pharmacol

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Advanced hormone-refractory prostate cancer is associated with poor prognosis and limited treatment options. Members of the pyrrolo-1,5-benzoxazepine (PBOX) family of compounds exhibit anti-cancer properties in cancer cell lines (including multi-drug resistant cells), ex vivo patient samples and in vivo mouse tumour models with minimal toxicity to normal cells.Recently, they have also been found to possess anti-angiogenic properties in vitro. However, both the apoptotic pathways and the overall extent of the apoptotic response induced by PBOX compounds tends to be cell-type specific. Since the effect of the PBOX compounds on prostate cancer has not yet been elucidated, the purpose of this study was to investigate if PBOX compounds induce anti-proliferative effects on hormone-refractory prostate cancer cells. We examined the effect of two representative PBOX compounds, PBOX-6 and PBOX-15, on the androgen-independent human prostate adenocarcinoma cell line, PC3. PBOX-6 and -15 displayed anti-proliferative effects on PC3 cells, mediated initially through a sustained G 2 /M arrest. G 2 /M arrest, illustrated as DNA tetraploidy, was accompanied by microtubule depolymerisation and phosphorylation of anti-apoptotic proteins Bcl-2 and Bclx L and the mitotic spindle checkpoint protein BubR1. Phosphorylation of BubR1 is indicative of an active mitotic checkpoint and results in maintenance of cell cycle arrest. G 2 /M arrest was followed by apoptosis illustrated by DNA hypoploidy and PARP cleavage and was accompanied by degradation of BubR1, Bcl-2 and Bcl-x L . Furthermore, sequential treatment with the CDK1-inhibitor, flavopiridol, synergistically enhanced PBOX-induced apoptosis. In summary, this in vitro study indicates that PBOX compounds may be useful alone or in combination with other agents in the treatment of hormone-refractory prostate cancer.3

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“…Suppression of BubR1 leads to deactivation of the spindle checkpoint and reduced nocodazole-induced cytotoxicity by compromising mitotic arrest (Greene et al, 2008). A mouse model of BubR1 haploinsufficiency showed enhanced genomic instability and tumorigenesis (Rao et al, 2005).…”

Section: Genomic Instability In Ebv-infected Cellsmentioning

confidence: 99%

Three Epstein–Barr virus latency proteins independently promote genomic instability by inducing DNA damage, inhibiting DNA repair and inactivating cell cycle checkpoints

2009

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BubR1 Is Required for a Sustained Mitotic Spindle Checkpoint Arrest in Human Cancer Cells Treated with Tubulin-Targeting Pyrrolo-1,5-Benzoxazepines

Abstract: Intrinsic or acquired resistance to chemotherapy is a major clinical problem that has evoked the need to develop innovative approaches to predict and ultimately reverse drug resistance. A prolonged G 2

Cited by 39 publications

References 31 publications

Antitumor effect of pyrrolo-1,5-benzoxazepine-15 and its synergistic effect with Oxaliplatin and 5-FU in colorectal cancer cells

Antitumor effect of pyrrolo-1,5-benzoxazepine-15 and its synergistic effect with Oxaliplatin and 5-FU in colorectal cancer cells

Dual targeting of tumour cells and host endothelial cells by novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines

Three Epstein–Barr virus latency proteins independently promote genomic instability by inducing DNA damage, inhibiting DNA repair and inactivating cell cycle checkpoints

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