Flavonoids as bio-regulators of human cells.

Flavonoids are a large chemical class in the plant kingdom, with over 5,000 different flavonoids described.  They are described as having a broad range of biological functions in plants, one such function being growth-regulation of plant cells including both inhibition and stimulation of cell proliferation.  Given the commonality in fundamental cellular processes between plant and animal cells, it is unsurprising that some flavonoids also display similar regulatory effects in both cell types, including modulation of cell cycle kinetics.  Quercetin, which is found in vegetables such as onions and apples and a common component of most human diets, is the most studied flavonoid in this regard.  Quercetin is a relatively potent regulator of such fundamental biochemical processes as NA+K+ATPase¹ and Ca2+ATPase², and reverse transcriptases.³   It was also the first inhibitor of protein tyrosine kinases (PTK) to be described,⁴ and as many of the PTKs are oncogenes, this raised the possibility of quercetin being an effective anti-cancer compound.  Quercetin was also found to be a potent inhibitor of phosphatidyl-3 kinase⁵ and 1-phosphatidylinositol-4 kinase,⁶ important enzymes in proliferation signaling pathways, ⁷ suggesting a potential for anti-proliferation.  Subsequently, quercetin was found to cause cell cycle arrest in late G1 phase of human leukemic T cells, and gastric, breast and ovarian cancer cells ^8-11.  Quercetin also is reported to induce apoptosis in cancer cells through a pathway involving the heat-shock proteins¹² as well as through down-regulation of the mutant p53 gene which can block apoptosis.¹³  Quercetin ultimately progressed to being tested as an intravenous agent in a Phase 1 study in cancer patients.  It was shown to achieve inhibition of lymphocyte tyrosine kinase activity as well as providing some evidence of anti-tumour activity.¹²   Short-term intravenous administration of this compound in DMSO was found to be well tolerated.Quercetin failed to progress into further clinical assessment, largely because other flavonoids possessed more potent anti-cancer activity.  One such flavonoid is genistein. Genistein is present in relatively high amounts in pulses such as soya, chick peas and lentils.  Genistein has been described as having anti-cancer activity in vitro against various types of human and animal cancers including melanoma,¹⁵ leukemia,^15-17 breast cancer,^18-22 gastrointestinal cancers,^23,24 prostate cancer²⁵ and neuroblastoma, Ewing's sarcoma and rhabdomyosarcoma.²⁶  Genistein, like quercetin, is a potent inhibitor of PTKs, preventing phosphorylation of PTKs at their receptor site; genistein inhibits most members of this large class of enzyme.^27,28  Genistein also is a potent inhibitor of DNA topoisomerases I and II.²⁹   The effect of these various enzyme-inhibitory actions is the down-regulation of various cellular processes and signal transduction mechanisms leading to mitotic arrest of cancer cells in the G2/M phase of mitosis,²⁴ induction of terminal differentiation of cancer cells^15,17,30 and induction of apoptosis.³¹  Genistein also displays a range of other biological effects with potential anti-cancer outcome including inhibition of angiogenesis³², and promotion of cancer cell adhesion.³³  Genistein has undergone clinical trials as an oral chemotherapeutic for a range of cancers.  The flavonoid to receive the greatest attention as a potential anti-cancer agent has been flavopiridol (Aventis).  This semi-synthetic compound (a N-methylpiperinidyl, chlorophenyl flavone) is based on a naturally-occurring plant flavonoid, rohitukine, and is a potent cyclin-dependent kinase inhibitor capable of producing mitotic arrest in either G1 or G2.³⁴   Flavopiridol exhibits anti-proliferative activity in vitro against a broad range of human cancer cells including non-small cell lung cancer cells³⁵ and prostate cancer and melanoma cells.³⁶  Flavopiridol has undergone clinical studies as an intravenous chemotherapeutic for head and neck cancer, prostatic carcinoma and chronic myeloid leukemia in particular (24 clinical trials are listed at www.clinicaltrials.gov.   Flavopiridol is administered by intravenous infusion dissolved in the carrier hydroxypropyl-b-cylcodextrin.  While early studies have revealed promising anti-cancer activity, flavopiridol has dose-limiting toxicity, the main side-effects being nausea, diarrhoea, fatigue and a pro-inflammatory syndrome.

The conclusion from these various studies is that flavonoids as a chemical class offer a potentially important and novel approach to cancer therapy. Studies of flavonoids to date indicate that they target and regulate a wide range of enzyme pathways and signal transduction mechanisms in human cells. The main outcomes of these effects are modulation of cell cycle kinetics, cell differentiation, and apoptosis. Flavonoids also appear to be relatively discriminating, acting predominantly on dysfunctional cells and thus pointing to a high level of safety.

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