The chemotherapeutic agent topotecan differentially modulates the phenotype and function of dendritic cells

Abstract

The camptothecin analogue topotecan (TPT) induces tumor cell apoptosis due to interference with topoisomerase I and is clinically used as a second-line chemotherapeutic in the treatment for metastasizing ovarian and small cell lung carcinoma. Based on the more recent finding of TPT-mediated inhibition of the transcription factor hypoxia-induced factor-1α, a hallmark of solid tumors, TPT, is currently tested in clinical trials for its suitability as a first-line chemotherapeutic for the treatment for various types of tumors. Due to the gained clinical interest in TPT and in light of its modulatory effect on signaling pathways, which are also of importance for immune cell functions, we asked for potential effects of TPT on dendritic cells (DCs), the main antigen-presenting cell population of the immune system. Here, we show that TPT at a therapeutically relevant dose partially activated monocyte-derived DCs as reflected by enhanced migratory activity, elevated expression of HLA-DR and costimulatory/maturation markers, and accordingly an increased allogenic CD4(+) T cell stimulation. In marked contrast, TPT prevented full maturation of DCs stimulated with a cocktail of proinflammatory mediators, accompanied by somewhat lower upregulation of NF-κB factors p65 and RelB.

Oxaliplatin regulates myeloid‐derived suppressor cell‐mediated immunosuppression via downregulation of nuclear factor‐κB signaling

“…In addition, anticancer agents may induce the activation of immune cells directly . Some anticancer drugs deplete proliferating immune cells at cytotoxic doses, while they augment the immunogenicity of immune cells at sublethal doses …”

“…2 Some anticancer drugs deplete proliferating immune cells at cytotoxic doses, while they augment the immunogenicity of immune cells at sublethal doses. 3,4 Chemotherapeutic agents are administered to cancer patients to eliminate cancer cells but are also known to generate adverse effects, including the depletion of dividing immune cells. Herein, we have examined the effect of anticancer drugs at sublethal doses on the immune systems of tumor bearing mice.…”

Connecting Prognostic Ligand Receptor Signaling Loops in Advanced Ovarian Cancer

“…In the context of chemotherapy, assessing the prognostic importance of signal transduction is an appealing avenue for biomarker development relevant for ovarian cancers: nearly 75% of cases eventually fail surgical control with primary platinum/taxane adjuvant chemotherapy [12] and common second-line treatments (gemicitabine [15], topotecan [16]) show differences in immune effect/response.…”

Triggering of Suicidal Erythrocyte Death by Topotecan

“…Topotecan is effective against tumor cells in part by triggering apoptosis [1,[25][26][27][28][29][30][31][32][33]. The cytotoxicity of topotecan has been attributed to inhibition of topoisomerase I [1,[33][34][35][36][37], double-stranded DNA damage [8,33], down-regulation of the transcription factors MycN [38], NF-κB [30] and HIF-1α [36], suppression of PTEN [32], VEGF [36] and Bcl-2 expression [31,37], oxidative stress [25], decrease of Akt activity [36], as well as caspase activation [25-27, 33, 37].…”

“…The camptothecin analogue [1] topotecan is utilized for the treatment of malignancy, such as ovarian cancer [2][3][4][5][6][7], cervical cancer [5,[8][9][10], retinoblastoma [11][12][13], small cell lung cancer [14][15][16][17][18], hematopoietic cell malignancy [19,20] and Wilms' tumor [21]. It is applied at a dosage of 10 mg/kg b.w.…”