Paclitaxel-Induced Epidermal Alterations: An In Vitro Preclinical Assessment in Primary Keratinocytes and in a 3D Epidermis Model

Abstract

Paclitaxel is a microtubule-stabilizing chemotherapeutic agent approved for the treatment of ovarian, non-small cell lung, head, neck, and breast cancers. Despite its beneficial effects on cancer and widespread use, paclitaxel also damages healthy tissues, including the skin. However, the mechanisms that drive these skin adverse events are not clearly understood. In the present study, we demonstrated, by using both primary epidermal keratinocytes (NHEK) and a 3D epidermis model, that paclitaxel impairs different cellular processes: paclitaxel increased the release of IL-1α, IL-6, and IL-8 inflammatory cytokines, produced reactive oxygen species (ROS) release and apoptosis, and reduced the endothelial tube formation in the dermal microvascular endothelial cells (HDMEC). Some of the mechanisms driving these adverse skin events in vitro are mediated by the activation of toll-like receptor 4 (TLR-4), which phosphorylate transcription of nuclear factor kappa B (NF-κb). This is the first study analyzing paclitaxel effects on healthy human epidermal cells with an epidermis 3D model, and will help in understanding paclitaxel’s effects on the skin.

Treatment for taxane‐resistant cutaneous angiosarcoma: A multicenter study of 50 Japanese cases

“…Paclitaxel and docetaxel, taxane anticancer agents, induce tumor cytotoxicity, as well as anti‐angiogenetic reactions 10–15 . Both paclitaxel and docetaxel increase the production of reactive oxygen species (ROS), 10–12 leading to reduced endothelial tube formation in dermal microvascular endothelial cells (HDMECs) 10 .…”

The Protective Anticancer Effect of Natural Lycopene Supercritical CO2 Watermelon Extracts in Adenocarcinoma Lung Cancer Cells

“…In this context, both the activation of NF-kB that plays an important role in controlling cell survival and apoptosis and the consequent release of proinflammatory cytokines, such as IL-8, can be considered the bridge between inflammation, cancer and oxidative stress [ 59 , 60 , 61 ]. It has already been assessed, in the context of chemoprevention, that the redox-sensitive transcription factors NF-κB and IL-8 are inflammatory signaling mediators involved in oxidative stress either in human respiratory epithelial cells or in cancer epidermal alterations [ 62 , 63 ]. A recent study performed both with primary epidermal keratinocytes and in a 3D epidermis model showed that a chemotherapeutic agent, also approved for the treatment of NSCLC, induced an increased rate of oxidative stress, inflammation and apoptosis via the upregulation of both NF-κB and IL-8 expression [ 62 ].…”

“…It has already been assessed, in the context of chemoprevention, that the redox-sensitive transcription factors NF-κB and IL-8 are inflammatory signaling mediators involved in oxidative stress either in human respiratory epithelial cells or in cancer epidermal alterations [ 62 , 63 ]. A recent study performed both with primary epidermal keratinocytes and in a 3D epidermis model showed that a chemotherapeutic agent, also approved for the treatment of NSCLC, induced an increased rate of oxidative stress, inflammation and apoptosis via the upregulation of both NF-κB and IL-8 expression [ 62 ]. Furthermore, other studies assessed that IL-8 expression correlated with ROS production, with ROS-induced mitochondrial damage and with the pro-apoptotic activity of chemopreventive agents, by demonstrating an increased expression of IL-8 in both human breast cancer and neuroblastoma cell [ 49 , 50 ].…”

“…In this latter condition, carotenoids, and particularly lycopene, can be protective against cancer. As carotenoids, another antioxidant category, such as polyphenols, can exert antioxidant or pro-oxidant cytotoxic effects, by low or high level of ROS production, depending on their endogenous concentration [ 62 ]. In this context, another of our previous pre-clinical studies on the effect of antioxidants on lung cancer, performed also with the A549 cell line [ 41 ], showed the role played by the flavonoid apigenin and the adipocytokine leptin in cell survival.…”

Expression of TRIM44 and its correlation with TLR4 in laryngeal squamous cell carcinoma

“…Numerous studies have shown that TLR4 is involved in mediating inflammation and immunity (36) and in regulating tumorigenesis and tumor progression (37). For example, TLR4 may promote the immune escape of human lung cancer cells and support ovarian cancer progression (38,39). Knockdown of TLR4 has been reported to inhibit the growth of human NSCLC cancer cells (40).…”