Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce apoptosis in multi-drug-resistant cancer cells

Nathwani, Seema-Maria; Butler, Stephen A.; Fayne, Darren; McGovern, Naomi; Sarkadi, Balázs; Meegan, Mary J.; Lloyd, David G.; Campiani, Giuseppe; Lawler, Mark; Williams, David C.; Zisterer, Daniela M.

doi:10.1007/s00280-009-1200-9

Cited by 28 publications

(30 citation statements)

References 32 publications

(47 reference 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%

“…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%

“…In addition, we have also found that PBOXs displayed antiangiogenic properties in vitro (10). An added advantage of PBOX compounds over many clinically used anti-cancer agents such as docetaxel is that they do not appear to be sub- ONCOLOGY REPORTS 24: 1499-1507 Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce cell cycle arrest and apoptosis in prostate cancer cells strates of the ABC-transporters, P-glycoprotein and BCRP, since they are capable of inducing apoptosis in multidrugresistant cancer cells expressing these transporters with similar efficacy as in transporter-negative drug-sensitive cells (14). The PBOX compounds exert their effects by binding to an uncharacterised site on tubulin resulting in microtubule depolymerisation (15).…”

Section: Introductionmentioning

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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

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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“…In addition we have also found that PBOXs displayed anti-angiogenic properties in vitro (10). An added advantage of PBOX compounds over many clinically used 4 anti-cancer agents such as docetaxel is that they do not appear to be substrates of the ABCtransporters, P-glycoprotein and BCRP, since they are capable of inducing apoptosis in multidrug-resistant cancer cells expressing these transporters with similar efficacy as in transporter-negative drug-sensitive cells (14). The PBOX compounds exert their effects by binding to an uncharacterised site on tubulin resulting in microtubule depolymerisation (15).…”

Section: Introductionmentioning

confidence: 61%

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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“…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%

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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Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce apoptosis in multi-drug-resistant cancer cells

Abstract: Our results suggest that pro-apoptotic PBOX compounds may be potential candidates for the treatment of P-glycoprotein- or BCRP-associated MDR cancers.

Cited by 28 publications

References 32 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

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

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