Vinata B. Lokeshwar, Division of Urology Research, Department of Urology (M-800), University of Miami Miller School of Medicine, P.O. Box 016960, Miami, FL 33101. Phone: 305-243-6321; Fax: 305-243-6893; E-mail: vlokeshw@med.miami.edu.


4-Methylumbelliferone (4-MU) is a hyaluronic acid (HA) synthesis inhibitor with anticancer properties; the mechanism of its anticancer effects is unknown. We evaluated the effects of 4-MU on prostate cancer cells. 4-MU inhibited proliferation, motility, and invasion of DU145, PC3-ML, LNCaP, C4-2B, and/or LAPC-4 cells. At IC50 for HA synthesis (0.4 mmol/L), 4-MU induced >3-fold apoptosis in prostate cancer cells, which could be prevented by the addition of HA. 4-MU induced caspase-8, caspase-9, and caspase-3 activation, PARP cleavage, upregulation of Fas-L, Fas, FADD and DR4, and downregulation of bcl-2, phosphorylated bad, bcl-XL, phosphorylated Akt, phosphorylated IKB, phosphorylated ErbB2, and phosphorylated epidermal growth factor receptor. At IC50, 4-MU also caused >90% inhibition of NF-κB reporter activity, which was prevented partially by the addition of HA. With the exception of caveolin-1, HA reversed the 4-MU–induced downregulation of HA receptors (CD44 and RHAMM), matrix-degrading enzymes (MMP-2 and MMP-9), interleukin-8, and chemokine receptors (CXCR1, CXCR4, and CXCR7) at the protein and mRNA levels. Expression of myristoylated-Akt rescued 4-MU–induced apoptosis and inhibition of cell growth and interleukin-8, RHAMM, HAS2, CD44, and MMP-9 expression. Oral administration of 4-MU significantly decreased PC3-ML tumor growth (>3-fold) when treatment was started either on the day of tumor cell injection or after the tumors became palpable, without organ toxicity, changes in serum chemistry, or body weight. Tumors from 4-MU–treated animals showed reduced microvessel density (∼3-fold) and HA expression but increased terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling–positive cells and expression of apoptosis-related molecules. Therefore, the anticancer effects of 4-MU, an orally bioavailable and relatively nontoxic agent, are primarily mediated by inhibition of HA signaling



Vinata B. Lokeshwar, Division of Urology Research, Department of Urology (M-800), University of Miami Miller School of Medicine

Vinata is a leading 4-MU (HEPARVIT) researcher, investigating its anti-tumour effects. With funding from the US Department of Defence, her research focus has been on Prostate and Bladder Cancer.

Vinata has been working with 4-MU (HEPARVIT) since 2005, having taken a keen interest in BioMonde research.

Whilst the anti-tumour mechanism remains unknownn and subjective,  European, USA, and Japanese research  have successfully linked HA inhibitation and 4-MU in numerous Cancers since 2000.  Vinata has taken the HA/4-MU research into the second decade of the 21st Century.