Abstract
Objective: Swertia chirata forms a rich source of bio-active compounds, among which xanthones form an important part. Among the xanthones present in it, 1,5,8 Tri-hydroxy-3-methoxy xanthone (TMX) was found to be the most active. The present study aims to evaluate the chemotherapeutic potential of it against metastatic skin cancer cell lines.
 Methods: In this study, the antitumor activity of TMX (the active component of chirata plant) was evaluated in A431, SKMEL-5, and A375 cell line by using in-vitro assays such as cell viability assay, cell cycle analysis, caspase 3 activity assay, intracellular reactive oxygen species (ROS) level determination by dichlorofluorescein diacetate, and quantitative real-time polymerase chain reaction (qRT-PCR).
 Results: In vitro studies showed that TMX from S. chirata exhibited significant antitumor activity by inducing apoptosis and restricting proliferation in both melanoma and non-melanoma skin cancer cell lines, but no such activity was seen in normal skin cancer cell line WS1. The qRT-PCR analysis revealed that in both the melanoma ad non-melanoma cell lines, TMX could exert its antitumor activity by downregulating c-Myc, cyclin-D1, and β-catenin and up-regulating Wnt antagonist gsk-3β, thereby suppressing wnt self-renewal pathway, but such regulation was absent in normal cell line.
 Conclusions: TMX from chirata could effectively inhibit the proliferation of metastatic skin cancer (both melanoma and non-melanoma) cell lines while being non-toxic to normal cell lines. The chemotherapeutic potential of TMX against metastatic skin cancer cell lines was achieved by downregulating several key regulatory genes enabling the suppression of the self-renewal pathway, the chief reason behind the invasiveness of cancer cells.
Highlights
Skin cancer is the most prevalent among all human cancers
These oncogenes play a crucial role in the maintenance of cancer stem cells (CSCs), which play a nodal role in metastasis [5]
IC50 for cancer cells was seen at a low concentration of 5 μM for SKMEL-5, 4 μM for A375, and 2 μM for A431 at 48 h, whereas normal cells showed 98% viability at the highest concentration of 20 μM for 48 h
Summary
Skin cancer is the most prevalent among all human cancers. In 2020, more than 100,000 people in the U.S are expected to be diagnosed with either melanoma or non-melanoma skin cancer. Aberrant activation of Wnt/β-catenin signaling leads to a rise in the nuclear accumulation of β-catenin, which leads to transcription of oncogenes such as c-Myc and cyclin D1 Together, these oncogenes play a crucial role in the maintenance of cancer stem cells (CSCs), which play a nodal role in metastasis [5]. We found that TMX could restrict DMBA/ croton oil-induced carcinogenesis to mild dysplastic lesions at the low dosage of 20 μg/kg in Swiss albino mice and could significantly increase survivability (data not shown) These observations lead us to hypothesize that TMX could be efficacious against metastatic skin cancer while being non-toxic to normal cells. In this study, we aim to evaluate and elucidate the mechanism by which TMX could exert antitumor activity against SCC cell line A431 and melanoma cell lines SKMEL-5 and A375 while being non-toxic to normal cell line WS1
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