A novel C,D-spirolactone analogue of paclitaxel: autophagy instead of apoptosis as a previously unknown mechanism of cytotoxic action for taxoids

Trmčić, Milena; Matović, Radomir; Tovilović, Gordana; Ristić, Biljana; Trajkovič, Vladimir; Ferjancic, Zorana; Saičić, Radomir N.

doi:10.1039/c2ob25514f

Cited by 12 publications

(6 citation statements)

References 56 publications

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“…Herein we present novel significant findings demonstrating that inhibition of late stage autophagy by BAF-A1 enhanced PBOX-6 but not PBOX-15-induced apoptotic death. Recent studies demonstrated unique autophagy properties endowed by a C, D-spirolactone analogue of paclitaxel not shared with the parent compound highlighting the complexity of autophagy stimulation (43). Inhibition of the early stages of autophagy by 3-methyladenine did not augment PBOX-induced cell death (data not shown).…”

Section: Discussionmentioning

confidence: 94%

Inhibition of late-stage autophagy synergistically enhances pyrrolo-1,5-benzoxazepine-6-induced apoptotic cell death in human colon cancer cells

Greene

Nolan

Regan-Komito

et al. 2013

International Journal of Oncology

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The pyrrolo-1,5-benzoxazepines (PBOXs) are a novel group of selective apoptotic agents displaying promising therapeutic potential in both ex vivo chemotherapy-refractory patient samples and in vivo murine carcinoma models. In this report, we present novel data concerning the induction of autophagy by the PBOXs in adenocarcinoma-derived colon cancer cells. Autophagy is a lysosome-dependent degradative pathway recently associated with chemotherapy. However, whether autophagy facilitates cell survival in response to chemotherapy or contributes to chemotherapy-induced cell death is highly controversial. Autophagy was identified by enhanced expression of LC3B-II, an autophagosome marker, an increase in the formation of acridine orange-stained cells, indicative of increased vesicle formation and electron microscopic confirmation of autophagic structures. The vacuolar H+ ATPase inhibitor bafilomycin-A1 (BAF-A1) inhibited vesicle formation and enhanced the apoptotic potential of PBOX-6. These findings suggest a cytoprotective role of autophagy in these cells following prolonged exposure to PBOX-6. Furthermore, BAF-A1 and PBOX-6 interactions were determined to be synergistic and caspase-dependent. Potentiation of PBOX-6-induced apoptosis by BAF-A1 was associated with a decrease in the levels of the anti-apoptotic protein, Mcl-1. The data provide evidence that autophagy functions as a survival mechanism in colon cancer cells to PBOX-6-induced apoptosis and a rationale for the use of autophagy inhibitors to further enhance PBOX‑6‑induced apoptosis in colon cancer.

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Section: Discussionmentioning

confidence: 94%

Inhibition of late-stage autophagy synergistically enhances pyrrolo-1,5-benzoxazepine-6-induced apoptotic cell death in human colon cancer cells

Greene

Nolan

Regan-Komito

et al. 2013

International Journal of Oncology

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“…It results in the inability of chromosomes in achieving a metaphase spindle configuration, and the progression of mitosis and prolonged activation of the mitotic checkpoint triggers apoptosis or reversion to the G-phase of the cell cycle without cell division . This arrests the G2/M cell cycle, and the ratio of large cells is increased and the size distribution might be enlarged in paclitaxel-treated cells . Preventing polymerization of actin filaments might influence the tension of the cytoskeleton than prevent depolymerization because the cytoskeletal framework remains after drug treatment.…”

Section: Resultsmentioning

confidence: 99%

“…42 This arrests the G2/M cell cycle, and the ratio of large cells is increased and the size distribution might be enlarged in paclitaxel-treated cells. 43 Preventing polymerization of actin filaments might influence the tension of the cytoskeleton than prevent depolymerization because the cytoskeletal framework remains after drug treatment. Therefore, Lat A had a greater impact on the cell deformability in comparison to Pax, and they have different polymerization and depolymerization targets.…”

Section: Analytical Chemistrymentioning

confidence: 99%

Microfluidic Mechanotyping of a Single Cell with Two Consecutive Constrictions of Different Sizes and an Electrical Detection System

et al. 2019

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The mechanical properties of a cell, which include parameters such as elasticity, inner pressure, and tensile strength, are extremely important because changes in these properties are indicative of diseases ranging from diabetes to malignant transformation. Considering the heterogeneity within a population of cancer cells, a robust measurement system at the single cell level is required for research and in clinical purposes. In this study, a potential microfluidic device for high-throughput and practical mechanotyping were developed to investigate the deformability and sizes of cells through a single run. This mechanotyping device consisted of two different sizes of consecutive constrictions in a microchannel and measured the size of cells and related deformability during transit. Cell deformability was evaluated based on the transit and on the effects of cytoskeleton-affecting drugs, which were detected within 50 ms. The mechanotyping device was able to also measure a cell cycle without the use of fluorescent or protein tags.

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“…Recently, a C,D-spirolactone taxane (5) was reported to be able to stabilize MT (only 13 times less active than 1a) and to possess cytotoxic activity against U251 human glioma cells (IC 50 values were in the range of 4-8 μM vs. 0.25-0.5 μM for 1a). 9 In addition, it displayed a mechanistically distinct cytotoxic action in comparison with 1a, involving mTOR inhibition-dependent autophagy instead of the G 2 /M cell cycle block-associated apoptosis, which is the general mechanism of action for most classic MT-stabilizing agents. We hypothesize that the unique C,D-spiro ring in compound 5 would be responsible for its unusual mechanism.…”

Section: Introductionmentioning

confidence: 99%

A novel C,D-spirodioxene taxoid synthesized through an unexpected Pd-mediated ring cyclization

et al. 2016

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A novel C,D-spirodioxene taxoid (6) was prepared from paclitaxel (1a), with the key steps including an unexpected Pd-mediated ring cyclization. The anti-tubulin activity of 6 was decreased relative to that of 1a and a previously reported C,D-spirolactone taxane (5). These observations could be rationalized on the basis of molecular modeling results. To the best of our knowledge, this is the first example indicating that 1,4-dioxenes can be synthesized from a mono-allyl vicinal diol through a Wacker-type cyclization. This strategy may be applicable to the synthesis of other C,D-spiro taxoids.

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A novel C,D-spirolactone analogue of paclitaxel: autophagy instead of apoptosis as a previously unknown mechanism of cytotoxic action for taxoids

Cited by 12 publications

References 56 publications

Inhibition of late-stage autophagy synergistically enhances pyrrolo-1,5-benzoxazepine-6-induced apoptotic cell death in human colon cancer cells

Inhibition of late-stage autophagy synergistically enhances pyrrolo-1,5-benzoxazepine-6-induced apoptotic cell death in human colon cancer cells

Microfluidic Mechanotyping of a Single Cell with Two Consecutive Constrictions of Different Sizes and an Electrical Detection System

A novel C,D-spirodioxene taxoid synthesized through an unexpected Pd-mediated ring cyclization

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