Abstract
Malignant melanoma is an aggressive cancer that develops drug resistance leading to poor prognosis. Efficient delivery of chemotherapeutic drugs to the tumor tissue remains a major challenge in treatment regimens. Using murine (B16) and human (SK-MEL-28) melanoma cells, we investigated traditional cytotoxic agents in combination with cold physical plasma-derived oxidants. We report synergistic cytotoxicity of doxorubicin and epirubicin, and additive toxicity of oxaliplatin with plasma exposure in coefficient of drug interaction analysis. The combination treatment led to an increased DNA damage response (increased phosphorylation of ATM, γ-H2AX foci, and micronuclei formation). There was also an enhanced secretion of immunogenic cell death markers ATP and CXCL10 in cell culture supernatants following combination treatment. The observed synergistic effects in tumor cells was due to enhanced intracellular doxorubicin accumulation via upregulation of the organic cationic transporter SLC22A16 by plasma treatment. The doxorubicin uptake was reversed by pretreating cells with antioxidants or calcium influx inhibitor BTP2. Endoribonuclease-prepared siRNAs (esiRNA)-mediated knockdown of SLC22A16 inhibited the additive cytotoxic effect in tumor cells. SK-MEL 28 and THP-1 monocytes co-culture led to greater THP-1 cell migration and SK-MEL-28 cytotoxicity when compared with controls. Taken together, we propose pro-oxidant treatment modalities to sensitize chemoresistant melanoma cells towards subsequent chemotherapy, which may serve as therapeutic strategy in combination treatment in oncology.
Highlights
The incidence of cutaneous melanoma has been steadily increasing in Europe and worldwide in the last three decades[1]
Using human and murine tumorigenic melanoma cell lines, we found that combination treatment DOX, EPI, or OXA and plasma significantly increased tumor cell killing in two-dimensional (2D) and three-dimensional (3D) cultures
Plasma treatment exerts additive toxic effects in drugsensitized melanoma cells To test the toxicity of combination treatment using cold plasma-derived oxidants and anti-neoplastic agents, melanoma cells (B16F0, B16F10, and SK-MEL-28) were pretreated with increasing concentrations (0.01, 0.1, 1.0, and 10 μM) of DOX, EPI, VOR, or OXA
Summary
The incidence of cutaneous melanoma has been steadily increasing in Europe and worldwide in the last three decades[1]. Treatment against melanoma includes conventional chemotherapy[2], biochemotherapy (chemotherapy combined with interleukin-2 and interferon-α)[3], small molecules against mutant BRAF4, and immune checkpoint inhibitors (anti-CTL4 and anti-PD1)[5]. Despite advances in treatment approaches, tumor heterogeneity confers varying degree of resistance and survival advantages limiting disease-free survival in patients[6]. Different classes of anti-neoplastic agents are employed as the frontline defense against cancers[7]. Most of these agents target or alter DNA synthesis and repair mechanisms leading to cell cycle arrest and death[8]. Despite the effectiveness of these agents against multiple tumors, Official journal of the Cell Death Differentiation Association
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