Dual inhibition of topoisomerases enhances apoptosis in melanoma cells

Abstract

The cytotoxicity of topoisomerase I inhibiting camptothecin, topoisomerase II inhibiting etoposide and their combination were investigated in wild type p53 Bowes and mutant p53 SK-MEL-28 melanoma cell lines during 24h. A combination of camptothecin and etoposide (1 μg/ml + 10 μg/ml) proved to be efficient in both types of cell lines, although mutant p53 cells exhibited a higher resistance. Further studies proved that in Bowes cells, a combination of drugs induced p53-dependent mitochondrial apoptosis characterized by activation of caspases-8 and -2, -9 and -3 with some concurrent involvement of oxidative stress. In SK-MEL-28 cells, apoptosis was found to be mediated via increased oxidative stress, activation of stress kinases such as p38 and SAPK/JNK and mitochondrial dysfunction without significant involvement of p53 and its transactivated target genes. These results demonstrate efficiency of dual inhibition of topoisomerases in melanoma cells with functional as well as mutant p53 and point out at possible further investigation of this modality in preclinical and clinical oncology.

FTY720 and cisplatin synergistically induce the death of cisplatin-resistant melanoma cells through the downregulation of the PI3K pathway and the decrease in epidermal growth factor receptor expression

“…Other studies have indicated that SK1 is downregulated by genotoxic stress and proteolysis of p53 induced by caspases (27,28). The resistant melanoma cell line, SK-Mel-28, harbors a p53 mutation, and cell death induced by anticancer drugs is independent of p53 (29). In the present study, the expression of SK1, but not that of SK2, in the SK-Mel-28 cells was reduced following treatment with a combination of FTY720 and cisplatin, but not following treatment with cisplatin or FTY720 alone (Fig.…”

“…Previous studies have demonstrated that the interaction between FTY720 and the S1P 1 receptor blocks STAT3 signaling in B-cell lymphoma (30) and the FTY-720-induced apoptosis of renal cancer cells is mediated by the inhibition of ERK activation (13). Apoptosis induced by chemotherapeutic agents in SK-Mel-28 cells is mediated by the activation of stress kinases, such as p38 MAP kinase and SAPK/JNK (29), and by the increased expression of the transactivation factor, E2F-1 (31). Furthermore, accumulating evidence suggests that the PI3K/Akt pathway is related to chemoresistance, mainly through escape from apoptosis, and these signaling pathways promote cell survival and proliferation (32).…”

Suppression of dendritic cell maturation and T cell proliferation by synovial fluid myeloid cells from mice with autoimmune arthritis

“…Drug-induced DC apoptosis control was set up by culturing DCs alone with the apoptosis-inducing topoisomerase inhibitors camptothecin (10 μM) and etoposide (1 μM) (30,31) in the absence or presence of Z-VAD-FMK. Inhibitors were purchased from Calbiochem (Gibbstown, NJ) or Sigma-Aldrich.…”

Chemotherapy resistance mechanisms in advanced skin cancer

“…It has been targeted by various inhibitory chemotherapeutic agents such as camptothecin and its derivatives, which inhibit Topo I, and doxorubicin, etoposides, mitoxantrone which inhibit Topo II. 36,37 In melanoma, etoposide resistance has been associated both with mutation or deletion 38 and increased activity of Topo II. 39 However, Satherley et al could not establish an association of chemosensitivity with expression of Topo II in choroidal melanoma.…”