δ-Tocotrienol Oxazine Derivative Antagonizes Mammary Tumor Cell Compensatory Response to CoCl₂-Induced Hypoxia

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 p70S6kinase 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.

Enhanced Bioavailability and Anticancer Activity of Vitamin Analogs

“…Moreover, their anticancer activity was mediated by decreased phosphorylation of cell survival protein Akt and inflammatory mediator, NFkB. Moreover, compound 44 that is derivative of d-tocotrienol showed antihypoxic activity in vitro and in vivo [35].…”

Anticancer Agents in Combination with Statins

“…Vitamin E consists of eight isoforms and γ-tocotrienol is one of them bearing potent antitumor activity when tested in vitro [39][40][41]. It has very little or no toxicity on normal cells and so can be used in cancer treatment safely.…”

A Brief Journey of Tocotrienols as Anticancer Agents

“…When chemically induced tumor bearing rats were given a diet of corn oil, palm oil and soya bean oil, it was observed that palm oil fed rats have lower incidence of tumor appearance and also lower number of tumors compared to the other two groups [28]. In different set of studies, it was observed that the palm oil is the major source of Tocotrienols which are proven to be the potent in vitro anticancer agents [29][30][31]. Palm oil represents one of the most abundant natural sources of tocotrienols [31].…”