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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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Chemical structures of α-tocopherol, δ-tocotrienol, and the δ-tocotrienol oxazine derivative, 12-((R)-6,8-dimethyl-8-((3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienyl)-9,10-dihydrochromeno[5, 6-e] [1, 3]oxazin-2(1H, 3H, 8H)-yl)dodecan-1-ol) (compound 44).
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fig1: Chemical structures of α-tocopherol, δ-tocotrienol, and the δ-tocotrienol oxazine derivative, 12-((R)-6,8-dimethyl-8-((3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienyl)-9,10-dihydrochromeno[5, 6-e] [1, 3]oxazin-2(1H, 3H, 8H)-yl)dodecan-1-ol) (compound 44).

Mentions: Compound 44 is the oxazine derivatives of δ-tocotrienol. Preparation, structural verification, and classification of tocotrienol oxazine derivatives, particularly compound 44, were previously described in detail [23, 24]. Based on results obtained from previous studies, compound 44 was found to display the most potent anticancer activity in both cell culture and animal tumor models, as compared to its natural parent δ-tocotrienol compound [23, 24], and was therefore selected for further characterization of its effects on +SA mammary tumor cell compensatory response to CoCl2-induced hypoxia in both cell culture and syngeneic mouse mammary tumor models. Chemical structures of natural vitamin E isoforms, α-tocopherol and δ-tocotrienol, and the semisynthetic oxazine derivative of δ-tocotrienol are shown in Figure 1.


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)

Chemical structures of α-tocopherol, δ-tocotrienol, and the δ-tocotrienol oxazine derivative, 12-((R)-6,8-dimethyl-8-((3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienyl)-9,10-dihydrochromeno[5, 6-e] [1, 3]oxazin-2(1H, 3H, 8H)-yl)dodecan-1-ol) (compound 44).
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Chemical structures of α-tocopherol, δ-tocotrienol, and the δ-tocotrienol oxazine derivative, 12-((R)-6,8-dimethyl-8-((3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienyl)-9,10-dihydrochromeno[5, 6-e] [1, 3]oxazin-2(1H, 3H, 8H)-yl)dodecan-1-ol) (compound 44).
Mentions: Compound 44 is the oxazine derivatives of δ-tocotrienol. Preparation, structural verification, and classification of tocotrienol oxazine derivatives, particularly compound 44, were previously described in detail [23, 24]. Based on results obtained from previous studies, compound 44 was found to display the most potent anticancer activity in both cell culture and animal tumor models, as compared to its natural parent δ-tocotrienol compound [23, 24], and was therefore selected for further characterization of its effects on +SA mammary tumor cell compensatory response to CoCl2-induced hypoxia in both cell culture and syngeneic mouse mammary tumor models. Chemical structures of natural vitamin E isoforms, α-tocopherol and δ-tocotrienol, and the semisynthetic oxazine derivative of δ-tocotrienol are shown in Figure 1.

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