The Bcl-2/Bcl-XL/Bcl-w Inhibitor, Navitoclax, Enhances the Activity of Chemotherapeutic Agents <i>In Vitro</i> and <i>In Vivo</i>

Chen, Jun; Jin, Sha; Abraham, Vivek C.; Huang, Xiaoli; Liu, Bernard A.; Mitten, Michael J.; Nimmer, Paul; Lin, Xiaoyu; Smith, Morey L.; Shen, Yu; Shoemaker, Alexander R.; Tahir, Stephen K.; Zhang, Haichao; Ackler, Scott; Rosenberg, Saul H.; Maecker, Heather; Sampath, Deepak; Leverson, Joel D.; Tse, Chris; Elmore, Steven W.

doi:10.1158/1535-7163.mct-11-0415

Cited by 134 publications

(104 citation statements)

References 29 publications

(38 reference statements)

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“…However, primary human SCLC xenografts were less responsive, as were other SCLC lines in vitro (16). Recent studies have reported synergy between ABT-737 or its relative ABT-263 and cytotoxic drugs in a variety of tumor xenograft models (47,(49)(50)(51), including melanomas (52,53). The IC 50 values we observed for ABT-737 on NOXAoverexpressing melanoma cells in flat culture were comparable with those reported for ABT-737-sensitive SCLC and lymphoid malignancies (13).…”

Section: Discussionsupporting

confidence: 81%

“…A number of other cancer types are sensitive to ABT-737 and there is evidence that its addition to chemotherapy regimens is beneficial (15), particularly in combination with antineoplastic drugs that alter the activity of MCL-1 and NOXA (46,47). Two examples are melphalan and flavopiridol, which are both reported to repress MCL-1, for example, in lung carcinoma and myeloma cells (25,29).…”

Section: Discussionmentioning

confidence: 99%

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Modulation of NOXA and MCL-1 as a Strategy for Sensitizing Melanoma Cells to the BH3-Mimetic ABT-737

Lucas

Mohana-Kumaran

Lau

et al. 2012

Clinical Cancer Research

107

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Purpose: Drug resistance in melanoma is commonly attributed to ineffective apoptotic pathways. Inhibiting antiapoptotic BCL-2 and its relatives is an attractive strategy for sensitizing lymphoid malignancies to drugs but it has been largely unsuccessful for melanoma and other solid tumors. ABT-737, a smallmolecule BH3-mimetic, selectively inhibits BCL-2, BCL-XL, and BCL-w and shows promise for treating leukemia, lymphoma, and small-cell lung cancer. Melanoma cells are insensitive to ABT-737, but MCL-1 inhibition reportedly increases the sensitivity of other tumors to the compound.Experimental Design: The efficacy of MCL-1 and BFL-1 inhibition for sensitizing melanoma cells to ABT-737 was investigated by short hairpin RNA-mediated knockdown or overexpression of their antagonist NOXA in two-dimensional cell culture, a three-dimensional organotypic spheroid model, and an in vivo model.Results: MCL-1 downregulation or NOXA overexpression strongly sensitized melanoma cells to ABT-737 in vitro. NOXA-inducing cytotoxic drugs also strongly sensitized melanomas to ABT-737 but, surprisingly, not vice versa. The drugs most suitable are not necessarily those normally used to treat melanoma. Resistance to ABT-737 occurred quickly in three-dimensional melanoma spheroids through reduced NOXA expression, although experiments with both xenografts and three-dimensional spheroids suggest that penetration of ABT-737 into tumor masses may be the principal limitation, which may be obviated through use of more diffusible BH3-mimetics.Conclusion: Sensitization of tumors to BH3-mimetics by cytotoxic drugs that induce NOXA is a therapeutic strategy worth exploring for the treatment of melanoma and other solid cancers. Clin Cancer Res; 18(3); 783-95. Ó2011 AACR.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Modulation of NOXA and MCL-1 as a Strategy for Sensitizing Melanoma Cells to the BH3-Mimetic ABT-737

Lucas

Mohana-Kumaran

Lau

et al. 2012

Clinical Cancer Research

107

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“…Of these, 14 were classified as having strong synergy (Bliss sum greater than 250). We defined this value empirically, on the basis of data showing good combination effects in xenografts of SK-OV-3 cells (18). The cell lines that had high Bliss scores tended to have lower levels of paclitaxel (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…We find that both combinations result in growth inhibition levels that are greater than additive in the majority of cell lines tested. Paclitaxel was the superior combination agent, and more than half of the cell lines exhibited Bliss sums greater than 250, a value empirically determined to translate to in vivo models (18). All of the high synergy cell lines expressed measurable levels of Bcl-x L , whereas some of the low synergy cell lines did not.…”

Section: Discussionmentioning

confidence: 99%

Navitoclax (ABT-263) Reduces Bcl-xL–Mediated Chemoresistance in Ovarian Cancer Models

Wong¹,

Tan²,

Zha³

et al. 2012

Molecular Cancer Therapeutics

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To examine the potential of combining Bcl-2 family inhibitors with chemotherapy in ovarian cancer, we evaluated a panel of 27 ovarian cancer cell lines for response to the combination of navitoclax (formerly ABT-263) and paclitaxel or gemcitabine. The majority of cell lines exhibited a greater than additive response to either combination, as determined by the Bliss independence model, and more than 50% of the ovarian cell lines exhibited strong synergy for the navitoclax/paclitaxel combination. To identify biomarkers for tumors likely to respond to this combination, we evaluated the protein levels of intrinsic apoptosis pathway components. Bcl-x L seems necessary, but not sufficient, for navitoclax/paclitaxel synergy in vitro, suggesting that exclusion of patients whose tumors have low or undetectable Bcl-x L would enrich for patients responsive to the combination. We evaluated Bcl-x L levels in ovarian cancer tumor tissue from 40 patients (20 taxane responsive and 20 with poor response to taxane) and found that patients with high Bcl-x L were less sensitive to taxane treatment (10 of 12) Bcl-x L positive patients, P ¼ 0.014). These data support the use of navitoclax in combination with taxane-based therapy in ovarian cancer patients with high levels of Bcl-x L .

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“…Navitoclax has been shown to enhance the activity of chemotherapeutic agents (20)(21)(22)(23)(24). However, studies on its ability to enhance targeted therapy have been limited.…”

Section: Introductionmentioning

confidence: 99%

Bcl-2/Bcl-xL Inhibition Increases the Efficacy of MEK Inhibition Alone and in Combination with PI3 Kinase Inhibition in Lung and Pancreatic Tumor Models

Tan¹,

Wong²,

Nannini³

et al. 2013

Molecular Cancer Therapeutics

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Although mitogen-activated protein (MAP)-extracellular signal-regulated kinase (ERK) kinase (MEK) inhibition is predicted to cause cell death by stabilization of the proapoptotic BH3-only protein BIM, the induction of apoptosis is often modest. To determine if addition of a Bcl-2 family inhibitor could increase the efficacy of a MEK inhibitor, we evaluated a panel of 53 non-small cell lung cancer and pancreatic cancer cell lines with the combination of navitoclax (ABT-263), a Bcl-2/Bcl-x L (BCL2/BCL2L1) antagonist, and a novel MAP kinase (MEK) inhibitor, G-963. The combination is synergistic in the majority of lines, with an enrichment of cell lines harboring KRAS mutations in the high synergy group. Cells exposed to G-963 arrest in G 1 and a small fraction undergo apoptosis. The addition of navitoclax to G-963 does not alter the kinetics of cell-cycle arrest, but greatly increases the percentage of cells that undergo apoptosis. The G-963/navitoclax combination was more effective than either single agent in the KRAS mutant H2122 xenograft model; BIM stabilization and PARP cleavage were observed in tumors, consistent with the mechanism of action observed in cell culture.

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The Bcl-2/Bcl-XL/Bcl-w Inhibitor, Navitoclax, Enhances the Activity of Chemotherapeutic Agents In Vitro and In Vivo

Cited by 134 publications

References 29 publications

Modulation of NOXA and MCL-1 as a Strategy for Sensitizing Melanoma Cells to the BH3-Mimetic ABT-737

Modulation of NOXA and MCL-1 as a Strategy for Sensitizing Melanoma Cells to the BH3-Mimetic ABT-737

Navitoclax (ABT-263) Reduces Bcl-xL–Mediated Chemoresistance in Ovarian Cancer Models

Bcl-2/Bcl-xL Inhibition Increases the Efficacy of MEK Inhibition Alone and in Combination with PI3 Kinase Inhibition in Lung and Pancreatic Tumor Models

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