The pyrrolo-1,5-benzoxazepine, PBOX-6, inhibits the growth of breast cancer cells in vitro independent of estrogen receptor status and inhibits breast tumour growth in vivo

Greene, Lisa M.; Fleeton, Marina N.; Mulligan, Jude M.; Gowda, Chikkanna; Sheahan, B. J.; Atkins, Gregory J.; Campiani, Giuseppe; Nacci, Vito; Lawler, Mark; Williams, D.C.; Zisterer, Daniela M.

doi:10.3892/or.14.5.1357

Cited by 16 publications

(33 citation statements)

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“…These values are within a similar range (1-6 and 0.2-0.4 μM for PBOX-6 and -15, respectively) to those observed in other cell lines such as CML K562 cells, promyelocytic leukaemia HL60 cells, ovarian carcinoma A2780 cells and a range of mammary carcinoma cell lines (10,11,14,16). This reduction in PC3 cell proliferation was mediated through a significant G 2 /M arrest followed by treatment for 24 h in either fresh media (as a control) or media containing flavopiridol (0.1-0.5 μM).…”

Section: Discussionsupporting

confidence: 62%

“…These results are supported by studies revealing impaired growth of tumours in a mouse 4T1 breast carcinoma tumour model (11), and a CML mouse model (12) and apoptosis in ex vivo CML and chronic lymphocytic leukaemia (CLL) patient samples (12,13). Interestingly, these compounds exert only minimal toxicity to normal peripheral blood mononuclear cells (PBMCs) (8) or bone marrow cells (13).…”

Section: Introductionsupporting

confidence: 62%

“…Much of this resistance is thought to be mediated through expression of the multidrug-resistance transporter, P-glycoprotein or by microtubule alterations (21). In addition to inducing apoptosis in a variety of cancerous cell types (5-9) and impairing tumour growth in vivo (11,12), novel pyrrolo-1,5-benzoxazepine (PBOX) compounds possess the added benefit of inducing cytotoxicity in multidrug-resistant cancer cells expressing P-glycoprotein with similar potency as in P-glycoprotein-negative cancer cells (14). Furthermore, they appear to induce tubulin depolymerisation by binding to a novel as yet uncharacterized site on tubulin (15).…”

Section: Discussionmentioning

confidence: 99%

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Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce cell cycle arrest and apoptosis in prostate cancer cells

Nathwani

Cloonan²,

Stronach³

et al. 2010

Oncol Rep

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Abstract. 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 tend 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 antiproliferative 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 antiapoptotic proteins Bcl-2 and Bcl-x 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 PBOXinduced 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. IntroductionProstate cancer is the leading cause of cancer and the second leading cause of cancer-related deaths among men in Europe and the USA (1). Early diagnosis following widespread PSA screening has resulted in most patients presenting with localized tumours. These patients generally exhibit good survival rates following radiotherapy or surgery. However, a number of patients still progress to or are diagnosed with locally advanced or metastatic tumours. While androgendeprivation therapy can slow the development of advanced metastatic prostate cancer, most tumours will still progress within a few years to an androgen-independent state (2). At this stage, treatment options become limited. The current treatment of choice for patients with advanced hormonerefractory prostate cancer is docetaxel-based chemotherapy. While these treatments significantly improve the overall survival of patients (3,4), the prognosis still remains poor for patients presenting with advanced stage prostate cancer. Therefore, the development of improved treatments and combinations are required.Our research group have established that some members of the pyrrolo-1,5-benzoxazepine (PBOX) famil...

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Section: Discussionsupporting

confidence: 62%

Section: Introductionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

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Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce cell cycle arrest and apoptosis in prostate cancer cells

Nathwani

Cloonan²,

Stronach³

et al. 2010

Oncol Rep

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show abstract

“…These results are supported by studies revealing impaired growth of tumours in a mouse 4T1 breast carcinoma tumour model (11), in a CML mouse model (12) and apoptosis in ex vivo CML patient samples (12,13). Interestingly, these compounds exert only minimal toxicity to normal peripheral blood mononuclear cells (PBMCs) (8) or bone marrow cells (13).…”

Section: Introductionmentioning

confidence: 80%

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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“…Pyrrolo-1,5-benzoxazepines (PBOX) are a family of novel compounds, which we have previously shown to induce cell cycle arrest and apoptosis in leukemia cell lines (4,5) and inhibit tumor growth in an in vivo breast carcinoma model (6). More recently, we have shown that two of the more active members of the family, pyrrolo-1,5-benzoxazepine-6 (PBOX-6) and pyrrolo-1,5-benzoxazepine-15 (PBOX-15), cause depolymerization of microtubules and disassembly of tubulin in vitro (7).…”

Section: Introductionmentioning

confidence: 99%

The Novel Tubulin-Targeting Agent Pyrrolo-1,5-Benzoxazepine-15 Induces Apoptosis in Poor Prognostic Subgroups of Chronic Lymphocytic Leukemia

et al. 2009

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Pyrrolo-1,5-benzoxazepine-15 (PBOX-15) is a novel microtubule depolymerization agent that induces cell cycle arrest and subsequent apoptosis in a number of cancer cell lines. Chronic lymphocytic leukemia (CLL) is characterized by clonal expansion of predominately nonproliferating mature B cells. Here, we present data suggesting PBOX-15 is a potential therapeutic agent for CLL. We show activity of PBOX-15 in samples taken from a cohort of CLL patients (n = 55) representing both high-risk and low-risk disease. PBOX-15 exhibited cytotoxicity in CLL cells (n = 19) in a dose-dependent manner, with mean IC 50 of 0.55 μmol/L. PBOX-15 significantly induced apoptosis in CLL cells (n = 46) including cells with poor prognostic markers: unmutated IgV H genes, CD38 and zeta-associated protein 70 (ZAP-70) expression, and fludarabine-resistant cells with chromosomal deletions in 17p. In addition, PBOX-15 was more potent than fludarabine in inducing apoptosis in fludarabine-sensitive cells. Pharmacologic inhibition and small interfering RNA knockdown of caspase-8 significantly inhibited PBOX-15-induced apoptosis. Pharmacologic inhibition of c-jun NH 2 -terminal kinase inhibited PBOX-15-induced apoptosis in mutated IgV H and ZAP-70 −

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The pyrrolo-1,5-benzoxazepine, PBOX-6, inhibits the growth of breast cancer cells in vitro independent of estrogen receptor status and inhibits breast tumour growth in vivo

Cited by 16 publications

References 0 publications

Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce cell cycle arrest and apoptosis in prostate cancer cells

Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce cell cycle arrest and apoptosis in prostate cancer cells

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

The Novel Tubulin-Targeting Agent Pyrrolo-1,5-Benzoxazepine-15 Induces Apoptosis in Poor Prognostic Subgroups of Chronic Lymphocytic Leukemia

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