Hyaluronan oligosaccharides sensitize lymphoma resistant cell lines to

CORDO RUSSO ROSALÍA; GARCÍA MARIANA G; ALANIZ LAURA D; BLANCO GUILLERMO; ALVAREZ ELIDA; HAJOS SILVIA E

INTERNATIONAL JOURNAL OF CANCER. JOURNAL INTERNATIONAL DU CANCER.

Wiley-Liss

Lugar: N. Y., United States; Año: 2008 vol. 122 p. 1012 - 1018

0020-7136

Abstract Multidrug resistance (MDR) is one of the main reasons for failure of cancer therapy. It may be mediated by overexpression of ATP-dependent efflux pumps or by alterations in survival or apoptotic pathways. Fragments generated by enzymatic degradation of hyaluronan (oHA) were able to modulate growth and cell survival and sensitize MDR breast cancer cells to cytotoxic drugs. In this work the relationship between oHA and MDR in lymphoid malignancies was analyzed using murine lymphoma cell lines resistant to doxorubicin (LBR-D160) or vincristine (LBR-V160) and a sensitive line (LBR-). When the effect of oHA was evaluated, apoptosis levels were observed to be higher in the resistant cell lines than in the sensitive one. Besides, oHA sensitized LBRD160 and LBR-V160 to vincristine showing increased apoptosis induction when used in combination with vincristine. Native hyaluronan failed to increase apoptosis levels. As different survival factors could be modulated by hyaluronan, we investigated the PI3K/Akt pathway through phosphorylated Akt (p-Akt) and survivin expression. Our results showed that oHA decreased p-Akt in the three cell lines while survivin was down regulated only in LBR-V160. When Pgp function was evaluated, we observed that oHA were able to inhibit Pgp efflux in murine and in human resistant cell lines and that CD44 receptor would be involved in this effect. In summary, we report for the first time that oHA modulate MDR in lymphoma cells by decreasing p-Akt as well as Pgp activity, thus suggesting that oHA could be useful in combination with classical chemotherapy in MDR hematological malignancies.