A. Effects of Hyaluronan Oligosaccharides on Tumors
Many studies have demonstrated that HA plays an important role in tumor malignancy. Toole et al. (10) have shown that perturbation of endogenous HA-tumor cell interactions by overexpression of soluble CD44, an HA-binding protein, inhibits tumor growth in vivo. Moreover, they have reported that perturbation of endogenous HA-tumor cell interactions by HA oligosaccharides (~2.5 kDa) also inhibits tumor growth in vivo (11) as well as anchorage-independent growth of tumors in vitro (4). In addition, Ghatak et al. (4) have shown that treatment of malignant tumor cells with HA oligosaccharides induces apoptosis and stimulates caspase-3 activity under anchorage-independent conditions. In addition to that, they found that treatment with HA oligosacchari-des stimulates expression of the tensin homolog (PTEN), a phosphatase that degrades the major signaling product of phosphoinositide 3-kinase (PI3-kinase). The ability of tumor cells to grow in an anchorage-independent manner is linked to elevation of the PI3-kinase/Akt cell survival pathway in tumor cells. Suppression of the PI3-kinase/Akt pathway in tumor cells leads to decreased phosphorylation and thus activation of pro-apoptotic mediators, BAD and FKHR, and increased activity of caspase-3.
The interaction of HA with cell surface receptors for HA, CD44 and RHAMM transduces intracellular signals (12). HA oligosaccharides and certain HA-blocking anti-CD44 antisera replace the multivalent, high-affinity interaction between endogenous HA polymers and HA receptors with a low valency, low-affinity interaction, and this would be expected to lead to changes in HA receptor signaling (4). Endogenous HA-CD44 interaction is necessary for maintenance of elevated levels of this pathway in tumor cells and thus their survival. In conclusion, treatment with HA oligosaccharides induces apoptosis in tumor cells through disrupting the endogenous HA-CD44 interaction, followed by enhancement of PTEN expression and inhibition of PI3-kinase signaling (4).
Misra et al. (13) have shown that an increase in HA polymer production induces resistance in drug-sensitive tumor cells, whereas treatment with HA oligosaccharides sensitizes multidrug-resistant tumor cells to a variety of chemotherapeutic drugs, such as doxorubicin and taxol. This is also due to disruption of endogenous HA-CD44 interaction by HA oligosaccharides.
HA binds cell surface receptors for HA such as RHAMM and CD44. HA was shown to be useful as a carrier for a drug delivery system (DSS) to deliver the drug to cells expressing HA receptors. CD44 is expressed in many kinds of cells. However, CD44-positive cells do not necessarily bind HA (14). CD44 can gain HA-binding ability after its activation. Because HA receptors are overexpressed and activated in these cells (15,16), some kinds of tumor cells and lymphocytes in inflammation can strongly bind HA (17,18). Therefore, the application of HA as a DDS is also feasible in these cells.
A N-(2-hydroxypropyl) methacrylamide (HPMA)-HA polymeric DSS was used for targeted delivery of doxorubicin to cancer cells (19). In addition, superoxide dismutase (SOD) from bovine erythrocytes was conjugated with sodium hyaluronate with a mean molecular weight of 106 to have greater antiinflammatory activity in vivo (20). This conjugate exhibited much higher anti-inflammatory activity than HA or SOD alone in models of inflammatory disease such as ischemic edema of the foot-pad in mice, carrageenin-induced pleurisy and adjuvant arthritis in rats (20). Polyampholyte comb-type copolymers, consisting of a poly main chain, a DNA binding site and HA side chains, were prepared as DNA carriers targeting sinusoidal endothelial cells of the liver that express the HA receptor, HARE (21). This DNA-HA conjugate may be useful for targeted delivery of genes in gene therapy.
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