Therapeutic Efficacy of ABT-737, a Selective Inhibitor of BCL-2, in Small Cell Lung Cancer

Hann, Christine L.; Daniel, Vincent C.; Sugar, Elizabeth A.; Dobromilskaya, Irina; Murphy, Sara C.; Cope, Leslie; Lin, Xue; Hierman, Jared S.; Wilburn, Daniel L.; Watkins, D. Neil; Rudin, Charles M.

doi:10.1158/0008-5472.can-07-5031

Cited by 185 publications

(156 citation statements)

References 30 publications

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“…As a single agent ABT-737, a novel Bcl -2/ Bcl -xL inhibitor triggers apoptosis in various types of human cancers including multiple myeloma, leukemia, lymphoma and small cell lung cancer. [25][26][27][28][29] However, we [30][31][32] and others 33 have demonstrated that ABT-737 minimally inhibits cell growth in glioma when used as a single agent. The complexity of the interactions between cell surface receptors and downstream signaling targets has called into question the clinical utility of blocking any target in isolation, and the results of single agent-based strategies have to date been disappointing in patients with glioma.…”

Section: Introductionmentioning

confidence: 94%

Cucurbitacin-I inhibits Aurora kinase A, Aurora kinase B and survivin, induces defects in cell cycle progression and promotes ABT-737-induced cell death in a caspase-independent manner in malignant human glioma cells

Premkumar¹,

Jane

Pollack

2014

Cancer Biology & Therapy

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Abbreviations: BSA, bovine serum albumin; DMSO, dimethyl sulfoxide; EGFR, epidermal growth factor receptor; MTS,[3][4]]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H, tetrazolium; FITC, fluorescein isothiocyanate; NF-kB, nuclear factor kB; PI3K, Phosphatidylinositol 3-Kinase; PBS, phosphate-buffered saline; PAGE, polyacrylamide gel electrophoresis; PDGFR, platelet derived growth factor receptor; TBS, Tris-buffered saline; TRAIL, tumor necrosis factor-related apoptosis inducing ligand; PI, propidium iodide.Because STAT signaling is commonly activated in malignant gliomas as a result of constitutive EGFR activation, strategies for inhibiting the EGFR/JAK/STAT cascade are of significant interest. We, therefore, treated a panel of established glioma cell lines, including EGFR overexpressors, and primary cultures derived from patients diagnosed with glioblastoma with the JAK/STAT inhibitor cucurbitacin-I. Treatment with cucurbitacin-I depleted p-STAT3, p-STAT5, p-JAK1 and p-JAK2 levels, inhibited cell proliferation, and induced G2/M accumulation, DNA endoreduplication, and multipolar mitotic spindles. Longer exposure to cucurbitacin-I significantly reduced the number of viable cells and this decrease in viability was associated with cell death, as confirmed by an increase in the subG1 fraction. Our data also demonstrated that cucurbitacin-I strikingly downregulated Aurora kinase A, Aurora kinase B and survivin. We then searched for agents that exhibited a synergistic effect on cell death in combination with cucurbitacin-I. We found that cotreatment with cucurbitacin-I significantly increased Bcl -2/Bcl -xL family member antagonist ABT-737-induced cell death regardless of EGFR/PTEN/p53 status of malignant human glioma cell lines. Although >50% of the cucurbitacin-I plus ABT-737 treated cells were annexin V and propidium iodide positive, PARP cleavage or caspase activation was not observed. Pretreatment of z-VAD-fmk, a pan caspase inhibitor did not inhibit cell death, suggesting a caspaseindependent mechanism of cell death. Genetic inhibition of Aurora kinase A or Aurora kinase B or survivin by RNA interference also sensitized glioma cells to ABT-737, suggesting a link between STAT activation and Aurora kinases in malignant gliomas.

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Section: Introductionmentioning

confidence: 94%

Cucurbitacin-I inhibits Aurora kinase A, Aurora kinase B and survivin, induces defects in cell cycle progression and promotes ABT-737-induced cell death in a caspase-independent manner in malignant human glioma cells

Premkumar¹,

Jane

Pollack

2014

Cancer Biology & Therapy

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“…The clinical relevance of long-established SCLC cell lines is open to question (41), and SCLC patient-derived xenografts (PDX) have been demonstrated to better reflect the underwhelming clinical results seen with single-agent Navitoclax (42). To expand our results to a model that more accurately effects patients tumors, we assessed efficacy of GDC-0941 and Navitoclax in a SCLC CDX2 derived from circulating tumor cells (CTC) enriched prior to the donor patient's chemotherapy (30).…”

Section: Effect Of Combined Pi3k Inhibition and Bh3 Mimetic In Vivomentioning

confidence: 99%

Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Potter

Galvin

Brown

et al. 2016

Molecular Cancer Therapeutics

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Most small cell lung cancer (SCLC) patients are initially responsive to cytotoxic chemotherapy, but almost all undergo fatal relapse with progressive disease, highlighting an urgent need for improved therapies and better patient outcomes in this disease. The proapoptotic BH3 mimetic ABT-737 that targets BCL-2 family proteins demonstrated good single-agent efficacy in preclinical SCLC models. However, so far clinical trials of the BH3 mimetic Navitoclax have been disappointing. We previously demonstrated that inhibition of a PI3K/BMX cell survival signaling pathway sensitized colorectal cancer cells to ABT-737. Here, we show that SCLC cell lines, which express high levels of BMX, become sensitized to ABT-737 upon inhibition of PI3K in vitro, and this is dependent on inhibition of the PI3K-BMX-AKT/mTOR signaling pathway. Consistent with these cell line data, when combined with Navitoclax, PI3K inhibition suppressed tumor growth in both an established SCLC xenograft model and in a newly established circulating tumor cell-derived explant (CDX) model generated from a blood sample obtained at presentation from a chemorefractory SCLC patient. These data show for the first time that a PI3K/BMX signaling pathway plays a role in SCLC cell survival and that a BH3 mimetic plus PI3K inhibition causes prolonged tumor regression in a chemorefractory SCLC patient-derived model in vivo. These data add to a body of evidence that this combination should move toward the clinic.

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“…However, there is considerable variation in the sensitivities of different SCLC cell lines to this drug (18,19). Studies in a variety of cell types have suggested that indicators of sensitivity include low levels of Mcl-1 and high levels of Bcl-2, Bcl-X L , Bim, and Noxa expression (19)(20)(21)(22)(23)(24)(25). In particular, studies in SCLC have documented that decreased Mcl-1 expression (19,20) and amplification of a region of chromosome 18 containing both the BCL-2 and NOXA genes correlates with increased sensitivity to ABT-737 (24).…”

Section: Introductionmentioning

confidence: 99%

Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737

Hauck

Chao

Litz

et al. 2009

Molecular Cancer Therapeutics

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To understand the molecular basis for variable sensitivity to the BH3 mimetic drug ABT-737, the abundance of Bcl-2 family members was assayed in a panel of small cell lung cancer cell lines whose sensitivity varied over a 2-log range. Elevated Noxa and Bcl-2 levels directly correlated with sensitivity to ABT-737, whereas Mcl-1 levels were similar in all cell lines tested regardless of sensitivity. Transgenically enforced expression of Noxa but not Bcl-2 resulted in increased sensitivity to ABT-737 in multiple cell lines. This increase was especially pronounced in the H209 cell line in which expression of Noxa resulted in a proportionate decline in Mcl-1 expression. Although overexpression of Noxa enhanced sensitivity of the H526 and H82 cell lines to ABT-737, it did not result in altered Mcl-1 levels. Similarly, small interfering RNA-mediated knockdown of Noxa expression in the H146 cell line, which increased resistance to ABT-737, did not result in altered Mcl-1 levels. Therefore, three of four cell lines studied failed to show Noxa-mediated regulation of Mcl-1 expression. However, despite failure to regulate Mcl-1 levels, Noxa blocked binding of Bim to Mcl-1 following its release from Bcl-2 by ABT-737. Finally, we observed that a 24-hour incubation of the H526 and WBA cell lines with ABT-737 resulted in increased Noxa expression, suggesting that Noxa may play a direct role in ABT-737-mediated apoptosis. These results indicate that Noxa expression is the critical determinant of ABT-737 sensitivity and loss of Noxa-mediated regulation of Mcl-1 expression may be an important feature of small cell lung cancer biology. [Mol Cancer Ther 2009;8(4):883-92]

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Therapeutic Efficacy of ABT-737, a Selective Inhibitor of BCL-2, in Small Cell Lung Cancer

Cited by 185 publications

References 30 publications

Cucurbitacin-I inhibits Aurora kinase A, Aurora kinase B and survivin, induces defects in cell cycle progression and promotes ABT-737-induced cell death in a caspase-independent manner in malignant human glioma cells

Cucurbitacin-I inhibits Aurora kinase A, Aurora kinase B and survivin, induces defects in cell cycle progression and promotes ABT-737-induced cell death in a caspase-independent manner in malignant human glioma cells

Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737

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