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Histone deacetylase inhibitors restore toxic BH3 domain protein expression in anoikis-resistant mammary and brain cancer stem cells, thereby enhancing the response to anti-ERBB1/ERBB2 therapy.

Cruickshanks N, Hamed HA, Booth L, Tavallai S, Syed J, Sajithlal GB, Grant S, Poklepovic A, Dent P - Cancer Biol. Ther. (2013)

Bottom Line: AR mammary carcinoma cells had reduced expression of the toxic BH3 domain proteins BAX, BAK, NOXA, and PUMA.Knockdown of MCL-1 and BCL-XL caused necro-apoptosis in AR cells to a greater extent than in parental cells.These data argue that one mechanism to enhance the anti-tumor effect of chemotherapy could be HDACI pre-treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery; Virginia Commonwealth University; Richmond, VA USA.

ABSTRACT
The present studies focused on defining the mechanisms by which anoikis-resistant (AR) mammary carcinoma cells can be reverted to a therapy-sensitive phenotype. AR mammary carcinoma cells had reduced expression of the toxic BH3 domain proteins BAX, BAK, NOXA, and PUMA. In AR cells expression of the protective BCL-2 family proteins BCL-XL and MCL-1 was increased. AR cells were resistant to cell killing by multiple anti-tumor cell therapies, including ERBB1/2 inhibitor + MCL-1 inhibitor treatment, and had a reduced autophagic flux response to these therapies, despite similarly exhibiting increased levels of LC3II processing. Knockdown of MCL-1 and BCL-XL caused necro-apoptosis in AR cells to a greater extent than in parental cells. Pre-treatment of anoikis-resistant cells with histone deacetylase inhibitors (HDACIs) for 24 h increased the levels of toxic BH3 domain proteins, reduced MCL-1 levels, and restored/re-sensitized the cell death response of AR tumor cells to multiple toxic therapies. In vivo, pre-treatment of AR breast tumors in the brain with valproate restored the chemo-sensitivity of the tumors and prolonged animal survival. These data argue that one mechanism to enhance the anti-tumor effect of chemotherapy could be HDACI pre-treatment.

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Related in: MedlinePlus

Figure 1. Low and high dose lapatinib increase obatoclax toxicity. BT474 and GBM12 cells in triplicate were treated with vehicle (VEH, DMSO), lapatinib (lap, 1 μM or 100 nM), obatoclax (GX, 50 nM) or the drug combination. Cells were isolated as indicated 12, 24, and 48 h later and viability determined by trypan blue (± SEM, n = 3) #P < 0.05 less than corresponding value in WT cells ##P > 0.05 compared with vehicle treated cells; *P < 0.05 greater than vehicle control.
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Figure 1: Figure 1. Low and high dose lapatinib increase obatoclax toxicity. BT474 and GBM12 cells in triplicate were treated with vehicle (VEH, DMSO), lapatinib (lap, 1 μM or 100 nM), obatoclax (GX, 50 nM) or the drug combination. Cells were isolated as indicated 12, 24, and 48 h later and viability determined by trypan blue (± SEM, n = 3) #P < 0.05 less than corresponding value in WT cells ##P > 0.05 compared with vehicle treated cells; *P < 0.05 greater than vehicle control.

Mentions: Thus we compared the interaction between a relatively low dose of lapatinib and that of a 10-fold greater dose, together with the time required to cause similar levels of killing. Low dose lapatinib interacted with obatoclax in ERBB2+ BT474 breast and ERBB1+ GBM12 brain cancer cells to cause similar levels of killing when compared with higher dose lapatinib at the 12 h and 48 h time points (for BT474) and at the 24 h and 48 h time points (for GBM12), respectively (Fig. 1). Of note was that low dose lapatinib as a single agent was not particularly toxic in either of these ERBB2/ERBB1 addicted tumor cell types whereas a 10-fold higher dose of the drug caused a significant measurable level of single agent killing.


Histone deacetylase inhibitors restore toxic BH3 domain protein expression in anoikis-resistant mammary and brain cancer stem cells, thereby enhancing the response to anti-ERBB1/ERBB2 therapy.

Cruickshanks N, Hamed HA, Booth L, Tavallai S, Syed J, Sajithlal GB, Grant S, Poklepovic A, Dent P - Cancer Biol. Ther. (2013)

Figure 1. Low and high dose lapatinib increase obatoclax toxicity. BT474 and GBM12 cells in triplicate were treated with vehicle (VEH, DMSO), lapatinib (lap, 1 μM or 100 nM), obatoclax (GX, 50 nM) or the drug combination. Cells were isolated as indicated 12, 24, and 48 h later and viability determined by trypan blue (± SEM, n = 3) #P < 0.05 less than corresponding value in WT cells ##P > 0.05 compared with vehicle treated cells; *P < 0.05 greater than vehicle control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3926895&req=5

Figure 1: Figure 1. Low and high dose lapatinib increase obatoclax toxicity. BT474 and GBM12 cells in triplicate were treated with vehicle (VEH, DMSO), lapatinib (lap, 1 μM or 100 nM), obatoclax (GX, 50 nM) or the drug combination. Cells were isolated as indicated 12, 24, and 48 h later and viability determined by trypan blue (± SEM, n = 3) #P < 0.05 less than corresponding value in WT cells ##P > 0.05 compared with vehicle treated cells; *P < 0.05 greater than vehicle control.
Mentions: Thus we compared the interaction between a relatively low dose of lapatinib and that of a 10-fold greater dose, together with the time required to cause similar levels of killing. Low dose lapatinib interacted with obatoclax in ERBB2+ BT474 breast and ERBB1+ GBM12 brain cancer cells to cause similar levels of killing when compared with higher dose lapatinib at the 12 h and 48 h time points (for BT474) and at the 24 h and 48 h time points (for GBM12), respectively (Fig. 1). Of note was that low dose lapatinib as a single agent was not particularly toxic in either of these ERBB2/ERBB1 addicted tumor cell types whereas a 10-fold higher dose of the drug caused a significant measurable level of single agent killing.

Bottom Line: AR mammary carcinoma cells had reduced expression of the toxic BH3 domain proteins BAX, BAK, NOXA, and PUMA.Knockdown of MCL-1 and BCL-XL caused necro-apoptosis in AR cells to a greater extent than in parental cells.These data argue that one mechanism to enhance the anti-tumor effect of chemotherapy could be HDACI pre-treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery; Virginia Commonwealth University; Richmond, VA USA.

ABSTRACT
The present studies focused on defining the mechanisms by which anoikis-resistant (AR) mammary carcinoma cells can be reverted to a therapy-sensitive phenotype. AR mammary carcinoma cells had reduced expression of the toxic BH3 domain proteins BAX, BAK, NOXA, and PUMA. In AR cells expression of the protective BCL-2 family proteins BCL-XL and MCL-1 was increased. AR cells were resistant to cell killing by multiple anti-tumor cell therapies, including ERBB1/2 inhibitor + MCL-1 inhibitor treatment, and had a reduced autophagic flux response to these therapies, despite similarly exhibiting increased levels of LC3II processing. Knockdown of MCL-1 and BCL-XL caused necro-apoptosis in AR cells to a greater extent than in parental cells. Pre-treatment of anoikis-resistant cells with histone deacetylase inhibitors (HDACIs) for 24 h increased the levels of toxic BH3 domain proteins, reduced MCL-1 levels, and restored/re-sensitized the cell death response of AR tumor cells to multiple toxic therapies. In vivo, pre-treatment of AR breast tumors in the brain with valproate restored the chemo-sensitivity of the tumors and prolonged animal survival. These data argue that one mechanism to enhance the anti-tumor effect of chemotherapy could be HDACI pre-treatment.

Show MeSH
Related in: MedlinePlus