Novel chloroquine derivative suppresses melanoma cell growth by DNA damage through increasing ROS levels

Abstract

Melanoma is a fatal cancer with a significant feature of resistance to traditional chemotherapeutic drugs and radiotherapy. A mutation in the kinase BRAF is observed in more than 66% of metastatic melanoma cases. Therefore, there is an urgent need to develop new BRAF‐mutant melanoma inhibitors. High‐dose chloroquine has been reported to have antitumour effects, but it often induces dose‐limiting toxicity. In this study, a series of chloroquine derivatives were synthesized, and lj‐2‐66 had the best activity and was selected for further investigation. Furthermore, the anti‐BRAF‐mutant melanoma effect and mechanism of this compound were explored. CCK‐8 and colony formation assays indicated that lj‐2‐66 significantly inhibited the proliferation of BRAF‐mutant melanoma cells. Flow cytometry revealed that lj‐2‐66 induced G2/M arrest in melanoma cells and promoted apoptosis. Furthermore, lj‐2‐66 increased the level of ROS in melanoma cells and induced DNA damage. Interestingly, lj‐2‐66 also played a similar role in BRAF inhibitor‐resistant melanoma cells. In summary, we found a novel chloroquine derivative, lj‐2‐66, that increased the level of ROS in melanoma cells and induced DNA damage, thus leading to G2/M arrest and apoptosis. These findings indicated that lj‐2‐66 may become a potential therapeutic drug for melanoma harbouring BRAF mutations.

Evaluation of the Antitumor Activity of Quaternary Ammonium Surfactants

“…Furthermore, a study from 2022 documented that chloroquine (CQ) acted on A375 melanoma cells, triggering the induction of apoptosis caused by the permeabilization of the lysosome membrane. The onset of apoptosis activation is indicated by the ratio of Bax protein expression relative to the control [36]. The results obtained in previous studies prove that compounds targeting lysosomes are able to induce apoptosis by increasing the expression of the pro-apoptotic gene Bax and reducing the expression of the apoptosis inhibitor Bcl-2.…”