Inhibition of GSTpi Activity Increases the Sensitivity of MCL Cell Lines to Cisplatin, Cytarabin and Bortezomib, but Not Doxorubicin.

Preliminary data suggest drug resistance plays a major role in mantle cell lymphoma (MCL) and is linked to the aberrant expression of molecules such as Glutathion S-Transferase pi (GST pi) that catalyzes the nuclear conjugation of a broad variety of reactive electrophiles to the glutathion. We investigated in vitro the effect of the inhibition of GSTpi activity on the chemosensitivity of MCL cell lines by inhibiting the nuclear transport of GSTpi with Agaricus bisporus leptine (ABL).

Methods. Four MCL cell lines (Granta, NCEB, REC and UPN1) were analyzed for GSTP1 transcript expression by RT-PCR analysis and for GSTP1 genetic Ile105Val polymorphism. The effect of ABL on the 4 MCL cell lines viability was examined using cells pre-treated with ABL (40μg/ml) for 10 h followed by treatment with various concentrations of doxorubicin (DOX), cisplatin (CDDP), cytarabin and bortezomib for 48 h. The cell viability was estimated by MTT assay repeated three times.

Results. All the 4 cell lines expressed GSTPI transcript. Two of them (UPN1 and REC) were heterozygous for Ile105Val polymorphism, whereas NCEB and GRANTA were homozygous GSTP1-105Ile which has been correlated with an enzyme of high activity. DOX, CDDP, cytarabin and bortezomib have cytotoxic effects compared to non-treated cells, without any difference between the 4 MCL cell lines when considering their genetic polymorphism status. Co-administration of ABL caused a significant increasis of the cytotoxicity of CDDP and bortezomib in all cell lines (Student test: p between 0.0004 to 0.02 for CDDP; and p between 0.013 and 0.05 for velcade, depending on the cell lines). Co-administration of ABL caused an increasis of the cytotoxicity of cytarabin in 3 cell lines, the 4^th being actually tested. No influence of ABL was detected on the cytotoxic effect of DOX. The analysis of the nuclear and the cytoplasmic localizations of GSTpi is currently realized by immunohistochemistry.

Conclusion. These results suggest that inhibition of the nuclear transfer of GSTpi increases in vitro the MCL sensitivity to CDDP, cytarabin and velcade but not DOX.