FBA-TPQ, a novel marine-derived compound as experimental therapy for prostate cancer

Wang, Rui; Ezell, Scharri J.; Zhang, Yong; Wang, Wei; Rayburn, Elizabeth R.; Nadkarni, Dwayaja H.; Murugesan, Srinivasan; Velu, Sadanandan E.; Zhang, Ruiwen

doi:10.1007/s10637-009-9232-x

Cited by 27 publications

(27 citation statements)

References 26 publications

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“…Previous studies indicated that BA-TPQ had activity against various human cancer cell lines, and that it was especially effective against breast cancer cells [13-15]. The mechanism(s) of action of BA-TPQ were not examined previously, but studies of related compounds have indicated various possible mechanisms of action for the iminoquinone analogs, including inhibition of topoisomerase II, inhibition of cell survival/proliferation, inhibition of oncogene expression, and interference with hormone receptor signaling [13-15].…”

Section: Discussionmentioning

confidence: 99%

“…1a. In accord with studies of other natural-product based agents, the iminoquinone analogs exert a variety of anti-cancer activities, including inhibition of topoisomerase II [14], inhibition of cell survival/proliferation [13], inhibition of oncogene expression [15], and inhibition of androgen receptor expression [15]. Because preliminary studies indicated that BA-TPQ was highly effective against breast cancer cells [13, 14], the present study examined the compound’s in vivo anti-breast cancer activity, and further examine the mechanism(s) by which it exerts anti-cancer effects in vitro and in vivo .…”

Section: Introductionmentioning

confidence: 99%

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A novel synthetic iminoquinone, BA-TPQ, as an anti-breast cancer agent: in vitro and in vivo activity and mechanisms of action

Wang

Rayburn

Velu

et al. 2009

Breast Cancer Res Treat

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Herein we report our examination of the anti-breast cancer activity of a novel synthetic compound, 7-(benzylamino)-1, 3, 4, 8-tetrahydropyrrolo [4, 3, 2-de]quinolin-8(1H)-one (BA-TPQ). This agent is an analog of a naturally-occurring marine compound, and was found to be the most active out of more than 40 related compounds. We investigated the in vitro activity of BA-TPQ on the survival, proliferation, and apoptosis of breast cancer cells using the MTT and BrdUrd assays, and Annexin/Annexin-PI staining and flow cytometry. The in vivo anti-cancer effects of BA-TPQ were evaluated in xenograft models of breast cancer. Finally, the mechanisms of action of the compound were also assessed by cDNA microarrays, RT-PCR and Western blotting. In a dose-dependent manner, BA-TPQ inhibited cell growth and induced apoptosis and cell cycle arrest in human MCF-7 and MDA-MB-468 breast cancer cells in vitro, and showed in vivo efficacy in mice bearing MCF-7 or MDA-MB-468 xenograft tumors. We demonstrated that BA-TPQ modifies the expression of numerous molecules involved in cell cycle progression and apoptosis. Similar changes in protein expression were observed in vitro and in vivo, as determined by examination of cells and excised xenograft tumors. Our preclinical data indicate that BA-TPQ is a potential therapeutic agent for breast cancer that has multiple hormone-, Her2- and p53-independent mechanisms of action, providing a basis for further development of the compound as a novel anticancer agent.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A novel synthetic iminoquinone, BA-TPQ, as an anti-breast cancer agent: in vitro and in vivo activity and mechanisms of action

Wang

Rayburn

Velu

et al. 2009

Breast Cancer Res Treat

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“…After two weeks of selection with G418 (Invitrogen, Carlsbad, CA), the cells stably expressing PSA-luc were amplified and referred to as LN-PSA-luc. Luciferase reporter assay was carried out as previously described (42). Briefly, the cells were seeded in complete growth medium and were allowed to grow to 40–50% confluence, and then were fed phenol red-free RPMI1640 medium supplemented with 10% charcoal-stripped serum for 24h.…”

Section: Methodsmentioning

confidence: 99%

A Novel Sulindac Derivative Lacking Cyclooxygenase-Inhibitory Activities Suppresses Carcinogenesis in the Transgenic Adenocarcinoma of Mouse Prostate Model

Zhang

Wang

et al. 2010

Cancer Prevention Research

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Nonsteroidal anti-inflammatory drugs (NSAIDs) including sulindac are well-documented to be highly effective for cancer chemoprevention. However, their cyclooxygenase (COX) inhibitory activities cause severe gastrointestinal and cardiovascular toxicities, limiting their chronic use. Recent studies suggest that COX-independent mechanisms may be responsible for the chemopreventive benefits of the NSAIDs, and support the potential for development of a novel generation of sulindac derivatives lacking COX inhibition for cancer chemoprevention. A prototypic sulindac derivative with a N,N-dimethylammonium substitution, referred to as sulindac sulfide amide (SSA) was recently identified to be devoid of COX inhibitory activity yet displays much more potent tumor cell growth inhibitory activity in vitro compared to sulindac sulfide. In this study, we investigated the androgen receptor (AR) signaling pathway as a potential target for its COX-independent antineoplastic mechanism and evaluated its chemopreventive efficacy against prostate carcinogenesis using the TRAMP mouse model. The results showed that SSA significantly suppressed the growth of human and mouse prostate cancer cells expressing AR in strong association with G1 arrest, and decreased AR level and AR-dependent transactivation. Dietary SSA consumption from 6 to 24 weeks of age dramatically attenuated prostatic growth and suppressed AR-dependent glandular epithelial lesion progression via repressing cell proliferation in the TRAMP mice, whereas it did not significantly impact neuroendocrine carcinoma growth. Overall, the results suggest that SSA may be a chemopreventive candidate against prostate glandular epithelial carcinogenesis.

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“…Importantly, the BA-TPQ inhibition of tumor growth through down-regulation of MDM2 expression is independent of p53 status, demonstrating a broader range of anti-tumor effect even for the p53 mutant cancer cell lines [7]. However, despite its high potency against a variety of human cancer cell lines including breast and prostate tumors [8,9], the application of BA-TPQ has been limited by its poor solubility and low bioavailability. In addition, undesirable toxicity was observed in mice after administering BA-TPQ (a formulation of dispersed BA-TPQ in a mixture of PEG400/ethanol/0.9% saline [8,9].…”

Section: Introductionmentioning

confidence: 99%

“…However, despite its high potency against a variety of human cancer cell lines including breast and prostate tumors [8,9], the application of BA-TPQ has been limited by its poor solubility and low bioavailability. In addition, undesirable toxicity was observed in mice after administering BA-TPQ (a formulation of dispersed BA-TPQ in a mixture of PEG400/ethanol/0.9% saline [8,9]. Recent investigations identifying the potential sites of accumulation to elucidate the observed BA-TPQ toxicity have revealed a high accumulation of BA-TPQ in the lungs, kidneys, and spleen of the mice [10,11].…”

Section: Introductionmentioning

confidence: 99%

Highly efficient delivery of potent anticancer iminoquinone derivative by multilayer hydrogel cubes

et al. 2017

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We report a novel delivery platform for a highly potent anticancer drug, 7-(benzylamino)-3,4-dihydro-pyrrolo[4,3,2-de]quinolin-8(1H)-one (BA-TPQ), using pH- and redox-sensitive poly(methacrylic acid) (PMAA) hydrogel cubes of micrometer size as the encapsulating matrix. The hydrogels are obtained upon cross-linking PMAA with cystamine in PMAA/poly(N-vinylpyrrolidone) multilayers assembled within mesoporous sacrificial templates. The BA-TPQ-loaded hydrogels maintain their cubical shape and pH-sensitivity after lyophilization, which is advantageous for long-term storage. Conversely, the particles degrade in vitro in the presence of glutathione (5 mM) providing 80% drug release within 24 h. Encapsulating BA-TPQ into hydrogels significantly increases its transport via Caco-2 cell monolayers used as a model for oral delivery where the apparent permeability of BA-TPQ-hydrogel cubes was ~2-fold higher than that of BA-TPQ. BA-TPQ-hydrogel cubes exhibit better anticancer activity against HepG2 (IC50=0.52 μg/mL) and Huh7 (IC50=0.29 μg/mL) hepatoma cells with a 40% decrease in the IC50 compared to the non-encapsulated drug. Remarkably, non-malignant liver cells have a lower sensitivity to BA-TPQ-hydrogel cubes with 2-fold increased IC50 values compared to those of cancer cells. In addition, encapsulating BA-TPQ in the hydrogels amplifies the potency of the drug via down-regulation of MDM2 oncogenic protein and upregulation of p53 (a tumor suppressor) and p21 (cell proliferation suppressor) expression in HepG2 liver cancer cells. Moreover, enhanced inhibition of MDM2 protein expression by BA-TPQ-hydrogel cubes is independent of p53-status in Huh7 cells. This drug delivery platform of non-spherical shape provides a facile method for encapsulation of hydrophobic drugs and can facilitate the enhanced efficacy of BA-TPQ for liver cancer therapy.

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FBA-TPQ, a novel marine-derived compound as experimental therapy for prostate cancer

Cited by 27 publications

References 26 publications

A novel synthetic iminoquinone, BA-TPQ, as an anti-breast cancer agent: in vitro and in vivo activity and mechanisms of action

A novel synthetic iminoquinone, BA-TPQ, as an anti-breast cancer agent: in vitro and in vivo activity and mechanisms of action

A Novel Sulindac Derivative Lacking Cyclooxygenase-Inhibitory Activities Suppresses Carcinogenesis in the Transgenic Adenocarcinoma of Mouse Prostate Model

Highly efficient delivery of potent anticancer iminoquinone derivative by multilayer hydrogel cubes

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