Herbal nutraceuticals: safe and potent therapeutics to battle tumor hypoxia.

Purpose: Growing solid tumors mostly outstrip blood supply and become hypoxic (low oxygen supply). To survive under this pathological milieu, tumors overexpress a potent oncogenic factor, hypoxia-inducible factor-1α (HIF-1α). HIF-1α up-regulate HIF-1 signaling pathways and subsequently activate genes that promote cancer growth even under hypoxia. Also, HIF-1 pathway activation leads to aggressive tumor growth, metastasis, therapy resistance and ultimately poor patient prognosis as evidential by several clinical studies. Hence, targeting HIF-1 pathway is regarded as a promising strategy to treat cancer. To date, several synthetic HIF-1 pathway inhibitors have been developed to treat hypoxic tumors; however, they are clinically ineffective due to off-target effects, low potency and high toxicity. Hence, there is an urgent need to explore safe and promising drugs to combat hypoxic tumors.

Results: This article extensively reviews the therapeutic potential of various herbal nutraceuticals against wide varieties of hypoxic tumors. The inhibitory effects of each herbal nutraceutical on the pathological consequences of HIF-1 signaling pathway and also their ability to improve the response of hypoxic cancer cells to conventional cancer therapies are discussed. Furthermore, we have provided new directions to overcome challenges behind conducting in vivo and preclinical hypoxia research and developing herbal nutraceuticals into pharmaceuticals to treat cancer.

Conclusions: The present review strongly suggests that herbal nutraceuticals are highly effective in combating the oncogenic effects of the HIF-1 pathway in wide varieties of tumors. However, more in vivo studies using zebrafish as a model system and extensive clinical studies in cancer patients with elevated tumor HIF-1α levels are highly warranted to ascertain the effective utilization of herbal nutraceuticals as adjunct/ alternative medicine in clinical practice to treat cancer.