Thioredoxin‐1 as a biological predictive marker for selecting diffuse large B‐cell lymphoma patients for etoposide‐containing treatment

Abstract

ObjectiveIn diffuse large B‐cell lymphoma (DLBCL), there is an unmet medical need to select patients who would benefit from intensified frontline treatments such as adding etoposide to an R‐CHOP regimen.MethodsThe present work included a retrospective clinical analysis of two patient cohorts and an in vitro study. Primary biopsy samples from DLBCL patients treated with an etoposide‐containing high‐dose regimen (n = 37) and etoposide‐containing frontline treatment (n = 69, R‐CHOEP) were studied using immunohistochemical thioredoxin‐1 (Trx1) staining. Two DLBCL cell lines expressing Trx1 were cultured, and their expression was silenced using the small interfering RNA knockdown technique. Chemoresistance was tested with doxorubicin, etoposide, vincristine, prednisolone and carboplatin.ResultsThioredoxin‐1 knockdown sensitised DLBCL cells to doxorubicin (P < .0001) but decreased etoposide‐induced cell death (P < .00001). In DLBCL patients who received etoposide‐containing frontline treatment, low cytoplasmic Trx1 expression was associated with inferior 5‐year overall survival (46% vs 76%, P = .026) and disease‐specific survival (68% vs 90%, P = .026).ConclusionsStrong Trx1 expression appears to increase drug resistance to doxorubicin but sensitises cells to etoposide. This implies that Trx1 expression might be the first predictive biological marker to select the patients who might benefit from adding etoposide to R‐CHOP immunochemotherapy.

Expanding the armory for treating lymphoma: Targeting redox cellular status through thioredoxin reductase inhibition

“…Using in vitro experiments they showed that Trx1 knockdown could sensitize two DLBCL cell lines to doxorubicin, confirming the role of Trx1 in conferring doxorubicin resistance [20,60]. The authors, therefore, concluded that while Trx1 increased resistance of DLBCL cancers to doxorubicin, it may sensitize cells to respond to etoposide [60]. However further studies with higher patient numbers are needed to conclusively determine the role of Trx1 in conferring either resistance or sensitivity to different therapeutic agents in DLBCL.…”

“…Interestingly a follow-up study by Kari et al showed that patients receiving CHOEP therapy (CHOP combined with etoposide) had better outcomes if they had higher Trx1 protein levels [60]. Using in vitro experiments they showed that Trx1 knockdown could sensitize two DLBCL cell lines to doxorubicin, confirming the role of Trx1 in conferring doxorubicin resistance [20,60]. The authors, therefore, concluded that while Trx1 increased resistance of DLBCL cancers to doxorubicin, it may sensitize cells to respond to etoposide [60].…”

The Importance of Thioredoxin-1 in Health and Disease

“…Using immunohistochemical staining, Li and colleagues found that diffuse large Bcell lymphomas (DLBCL) have higher Trx-1 expression than normal B-cells [86], and that increased Trx expression is associated with poor progression-free survival [86,87]. Interestingly, Kari and colleagues observed that strong Trx-1 expression sensitized cells to etoposide, suggesting that Trx-1 could be used as a predictive biological marker for selecting patients who might benefit from the addition of etoposide to R-CHOP immunochemotherapy [88]. Shao et al demonstrated that Trx-1 levels were variable in children with acute T-cell lymphoblastic leukemia and that these cells had higher Trx-1 levels associated with higher white blood cell counts [89].…”