A novel chalcone derivative has antitumor activity in melanoma by inducing DNA damage through the upregulation of ROS products

Keke Li; Shuang Zhao; Jing Long; Juan Su; Lisha Wu; Juan Tao; Jianda Zhou; JiangLin Zhang; Xiang Chen; Cong Peng

doi:10.1186/s12935-020-1114-5

A novel chalcone derivative has antitumor activity in melanoma by inducing DNA damage through the upregulation of ROS products

Cancer Cell Int. 2020 Jan 30:20:36. doi: 10.1186/s12935-020-1114-5. eCollection 2020.

Authors

Keke Li^#^{1

2

3}, Shuang Zhao^#^{1

2

3}, Jing Long^#^{1

2

3}, Juan Su^{1

2

3}, Lisha Wu^{1

2

3}, Juan Tao⁴, Jianda Zhou⁵, JiangLin Zhang^{1

2

3}, Xiang Chen^{1

2

3}, Cong Peng^{1

2

3}

Affiliations

¹ 1The Department of Dermatology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan China.
² 2Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan China.
³ 3Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan China.
⁴ 4Department of Dermatology, Affiliated Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁵ 5Department of Plastic Surgery of Third Xiangya Hospital, Central South University, Changsha, China.

^# Contributed equally.

Abstract

Background: Melanoma is one of the most aggressive tumors with the remarkable characteristic of resistance to traditional chemotherapy and radiotherapy. Although targeted therapy and immunotherapy benefit advanced melanoma patient treatment, BRAFi (BRAF inhibitor) resistance and the lower response rates or severe side effects of immunotherapy have been observed, therefore, it is necessary to develop novel inhibitors for melanoma treatment.

Methods: We detected the cell proliferation of lj-1-59 in different melanoma cells by CCK 8 and colony formation assay. To further explore the mechanisms of lj-1-59 in melanoma, we performed RNA sequencing to discover the pathway of differential gene enrichment. Western blot and Q-RT-PCR were confirmed to study the function of lj-1-59 in melanoma.

Results: We found that lj-1-59 inhibits melanoma cell proliferation in vitro and in vivo, induces cell cycle arrest at the G2/M phase and promotes apoptosis in melanoma cell lines. Furthermore, RNA-Seq was performed to study alterations in gene expression profiles after treatment with lj-1-59 in melanoma cells, revealing that this compound regulates various pathways, such as DNA replication, P53, apoptosis and the cell cycle. Additionally, we validated the effect of lj-1-59 on key gene expression alterations by Q-RT-PCR. Our findings showed that lj-1-59 significantly increases ROS (reactive oxygen species) products, leading to DNA toxicity in melanoma cell lines. Moreover, lj-1-59 increases ROS levels in BRAFi -resistant melanoma cells, leading to DNA damage, which caused G2/M phase arrest and apoptosis.

Conclusions: Taken together, we found that lj-1-59 treatment inhibits melanoma cell growth by inducing apoptosis and DNA damage through increased ROS levels, suggesting that this compound is a potential therapeutic drug for melanoma treatment.

Keywords: Chalcone; DNA damage; Melanoma; P53; ROS (reactive oxygen species).