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δ-Tocotrienol oxazine derivative antagonizes mammary tumor cell compensatory response to CoCl2-induced hypoxia.

Ananthula S, Parajuli P, Behery FA, Alayoubi AY, Nazzal S, El Sayed K, Sylvester PW - Biomed Res Int (2014)

Bottom Line: In response to low oxygen supply, cancer cells elevate production of HIF-1α, a hypoxia-inducible transcription factor that subsequently acts to stimulate blood vessel formation and promote survival.Treatment with 150 µM CoCl2 induced a hypoxic response in +SA mammary tumor cells as evidenced by a large increase in HIF-1α levels, and combined treatment with compound 44 attenuated this response.Additional in vivo studies showed that intralesional treatment with compound 44 in BALB/c mice bearing +SA mammary tumors significantly decreased the levels of HIF-1α, and this effect was associated with a corresponding decrease in Akt/mTOR signaling and activation of downstream targets p70S6 kinase and eIF-4E1.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, University of Louisiana at Monroe, 700 University Avenue, Monroe, LA 71209-0470, USA.

ABSTRACT
In response to low oxygen supply, cancer cells elevate production of HIF-1α, a hypoxia-inducible transcription factor that subsequently acts to stimulate blood vessel formation and promote survival. Studies were conducted to determine the role of δ-tocotrienol and a semisynthetic δ-tocotrienol oxazine derivative, compound 44, on +SA mammary tumor cell hypoxic response. Treatment with 150 µM CoCl2 induced a hypoxic response in +SA mammary tumor cells as evidenced by a large increase in HIF-1α levels, and combined treatment with compound 44 attenuated this response. CoCl2-induced hypoxia was also associated with a large increase in Akt/mTOR signaling, activation of downstream targets p70S6K and eIF-4E1, and a significant increase in VEGF production, and combined treatment with compound 44 blocked this response. Additional in vivo studies showed that intralesional treatment with compound 44 in BALB/c mice bearing +SA mammary tumors significantly decreased the levels of HIF-1α, and this effect was associated with a corresponding decrease in Akt/mTOR signaling and activation of downstream targets p70S6 kinase and eIF-4E1. These findings demonstrate that treatment with the δ-tocotrienol oxazine derivative, compound 44, significantly attenuates +SA mammary tumor cell compensatory responses to hypoxia and suggests that this compound may provide benefit in the treatment of rapidly growing solid breast tumors.

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Related in: MedlinePlus

ELISA quantification of VEGF protein levels in the culture media following +SA mammary tumor cells exposed to 150 µM CoCl2 alone and in combination with compound 44. +SA cells were plated at a density of 5 × 103 cells/well in 96-well culture plates (6 replicates/group) in 96-well tissue culture plates and allowed to attach overnight. The next day, cells were divided into different groups and exposed to their respective treatments for a 24 hr incubation period. Afterward, cell media from wells in each treatment group and added to VEGF antibody coated 96-well plates for ELISA analysis. Vertical bars indicate mean VEGF levels (pg/mL) ± SEM. #P < 0.05 compared to the vehicle-treated control group. *P < 0.05 as compared to the hypoxic group treated with CoCl2 alone.
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fig7: ELISA quantification of VEGF protein levels in the culture media following +SA mammary tumor cells exposed to 150 µM CoCl2 alone and in combination with compound 44. +SA cells were plated at a density of 5 × 103 cells/well in 96-well culture plates (6 replicates/group) in 96-well tissue culture plates and allowed to attach overnight. The next day, cells were divided into different groups and exposed to their respective treatments for a 24 hr incubation period. Afterward, cell media from wells in each treatment group and added to VEGF antibody coated 96-well plates for ELISA analysis. Vertical bars indicate mean VEGF levels (pg/mL) ± SEM. #P < 0.05 compared to the vehicle-treated control group. *P < 0.05 as compared to the hypoxic group treated with CoCl2 alone.

Mentions: After a 24 hr treatment exposure to 150 µM CoCl2, +SA mammary tumor cell synthesis of VEGF was significantly increased as compared to cells in the vehicle-treated control group (Figure 7). Treatment with 2 μM of the δ-tocotrienol oxazine derivative, compound 44, alone had little or no effect on +SA mammary tumor cell VEGF synthesis as compared to the vehicle-treated control group (Figure 7). However, combined treatment of compound 44 resulted in a blockade of the CoCl2-dependent increase in VEGF synthesis in +SA cells (Figure 7).


δ-Tocotrienol oxazine derivative antagonizes mammary tumor cell compensatory response to CoCl2-induced hypoxia.

Ananthula S, Parajuli P, Behery FA, Alayoubi AY, Nazzal S, El Sayed K, Sylvester PW - Biomed Res Int (2014)

ELISA quantification of VEGF protein levels in the culture media following +SA mammary tumor cells exposed to 150 µM CoCl2 alone and in combination with compound 44. +SA cells were plated at a density of 5 × 103 cells/well in 96-well culture plates (6 replicates/group) in 96-well tissue culture plates and allowed to attach overnight. The next day, cells were divided into different groups and exposed to their respective treatments for a 24 hr incubation period. Afterward, cell media from wells in each treatment group and added to VEGF antibody coated 96-well plates for ELISA analysis. Vertical bars indicate mean VEGF levels (pg/mL) ± SEM. #P < 0.05 compared to the vehicle-treated control group. *P < 0.05 as compared to the hypoxic group treated with CoCl2 alone.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4129965&req=5

fig7: ELISA quantification of VEGF protein levels in the culture media following +SA mammary tumor cells exposed to 150 µM CoCl2 alone and in combination with compound 44. +SA cells were plated at a density of 5 × 103 cells/well in 96-well culture plates (6 replicates/group) in 96-well tissue culture plates and allowed to attach overnight. The next day, cells were divided into different groups and exposed to their respective treatments for a 24 hr incubation period. Afterward, cell media from wells in each treatment group and added to VEGF antibody coated 96-well plates for ELISA analysis. Vertical bars indicate mean VEGF levels (pg/mL) ± SEM. #P < 0.05 compared to the vehicle-treated control group. *P < 0.05 as compared to the hypoxic group treated with CoCl2 alone.
Mentions: After a 24 hr treatment exposure to 150 µM CoCl2, +SA mammary tumor cell synthesis of VEGF was significantly increased as compared to cells in the vehicle-treated control group (Figure 7). Treatment with 2 μM of the δ-tocotrienol oxazine derivative, compound 44, alone had little or no effect on +SA mammary tumor cell VEGF synthesis as compared to the vehicle-treated control group (Figure 7). However, combined treatment of compound 44 resulted in a blockade of the CoCl2-dependent increase in VEGF synthesis in +SA cells (Figure 7).

Bottom Line: In response to low oxygen supply, cancer cells elevate production of HIF-1α, a hypoxia-inducible transcription factor that subsequently acts to stimulate blood vessel formation and promote survival.Treatment with 150 µM CoCl2 induced a hypoxic response in +SA mammary tumor cells as evidenced by a large increase in HIF-1α levels, and combined treatment with compound 44 attenuated this response.Additional in vivo studies showed that intralesional treatment with compound 44 in BALB/c mice bearing +SA mammary tumors significantly decreased the levels of HIF-1α, and this effect was associated with a corresponding decrease in Akt/mTOR signaling and activation of downstream targets p70S6 kinase and eIF-4E1.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, University of Louisiana at Monroe, 700 University Avenue, Monroe, LA 71209-0470, USA.

ABSTRACT
In response to low oxygen supply, cancer cells elevate production of HIF-1α, a hypoxia-inducible transcription factor that subsequently acts to stimulate blood vessel formation and promote survival. Studies were conducted to determine the role of δ-tocotrienol and a semisynthetic δ-tocotrienol oxazine derivative, compound 44, on +SA mammary tumor cell hypoxic response. Treatment with 150 µM CoCl2 induced a hypoxic response in +SA mammary tumor cells as evidenced by a large increase in HIF-1α levels, and combined treatment with compound 44 attenuated this response. CoCl2-induced hypoxia was also associated with a large increase in Akt/mTOR signaling, activation of downstream targets p70S6K and eIF-4E1, and a significant increase in VEGF production, and combined treatment with compound 44 blocked this response. Additional in vivo studies showed that intralesional treatment with compound 44 in BALB/c mice bearing +SA mammary tumors significantly decreased the levels of HIF-1α, and this effect was associated with a corresponding decrease in Akt/mTOR signaling and activation of downstream targets p70S6 kinase and eIF-4E1. These findings demonstrate that treatment with the δ-tocotrienol oxazine derivative, compound 44, significantly attenuates +SA mammary tumor cell compensatory responses to hypoxia and suggests that this compound may provide benefit in the treatment of rapidly growing solid breast tumors.

Show MeSH
Related in: MedlinePlus