Benzohydrol derived compounds that induce a therapeutic response in cancer cells through the synergistic targeting of mitochondrial complex I and hypoxia inducible factor (HIF).
- Utilizes dual mechanisms of action for increased efficacy.
- Provides therapeutic window for selective targeting of cancer cells.
- Potent against glioblastoma, sarcoma and melanoma cell lines.
Therapeutic regimens available to clinicians cause extreme side effects and remain non-effective against chemo-resistant cancers that are commonly present in relapsed patients. A promising route for tackling these two recurring problems in chemotherapeutics is through the inhibition of the hypoxia inducible factor which is upregulated in cancer cells. Despite tremendous efforts, research toward developing HIF agents has not resulted in a significant anti-cancer compound and discovering an active HIF-targeted agent remains an unmet clinical need.
Upregulation of hypoxia inducible factor (HIF) is a direct indication of poor patient prognosis attributed to increased cancer progression, heightened invasiveness of tumors and an amplified resistance to chemo and radiotherapies. In cells with normal oxygen conditions, HIF is rapidly degraded by prolyl hydroxylase. In hypoxic cancer cells the activity of prolyl hydroxylase is diminished, meaning that the HIF protein is allowed to survive. This HIF protein leads to the transcription of various proteins that increase the proliferation of cancer cells in hypoxic conditions. Researchers at Emory University and Georgia State University have yielded several compounds that are highly potent against melanoma, sarcoma and glioblastoma cancer cells through the targeting of the HIF pathway. These compounds also act synergistically against cancer cell proliferation by inhibiting mitochondrial complex I, leading to ATP exhaustion, inhibition of phospho-protein signaling and cell death.
In vitro data demonstrating the effectiveness of the synergistic anti-cancer agents are available.