Co-Treatment of Chloroquine and Trametinib Inhibits Melanoma Cell Proliferation and Decreases Immune Cell Infiltration

Abstract

Autophagy is characterized as a cytoprotective process and inhibition of autophagy with medicinally active agents, such as chloroquine (CQ) is proposed as a prospective adjuvant therapy for cancer. Here, we examined the preclinical effects of CQ combined with the MEK inhibitor trametinib (TRA) on melanoma. We found that cotreatment of CQ and TRA markedly slowed melanoma growth induced in Tyr-CreER.BrafCa.Ptenfl/fl mice. Immunostaining showed that trametinib decreased Ki-67+ proliferating cells, and increased TUNEL+ apoptotic cells. The combo treatment induced a further decrease of Ki-67+ proliferating cells. Consistent with the in vivo findings, CQ and TRA inhibited melanoma cell proliferation in vitro, which was correlated by decreased cyclin D1 expression. In addition, we found that tissues treated with CQ and TRA had significantly decreased numbers of CD4+ and CD8+ T-lymphocytes and F4/80+ macrophages. Together, these results indicate that cotreatment of CQ and TRA decreases cancer cell proliferation, but also dampens immune cell infiltration. Further study is warranted to understand whether CQ-induced immune suppression inadvertently affects therapeutic benefits.

Pharmacology Progresses and Applications of Chloroquine in Cancer Therapy

“… 107 Autophagy also was induced in chemotherapeutics in melanoma and glioma, there was no doubt that CQ played important synergistic role in the chemotherapy of these tumors. 110 , 111 , 113 All these data affirmed the importance of autophagy for tumor cells, and autophagy inhibitor CQ was effective therapeutic strategy of human cancers.…”

“… MiaPaCa-2: 50 mg/kg Panc-1:100 mg/kg daily Melanoma A375, A2058, B16-F25 In vitro 10 µM Y Inhibited autophagy, cell proliferation, and weaken immune cell infiltration. [ 110 ] A375 In vivo I.p 40 mg/kg every other day Melanoma WM793, 1205Lu In vitro 50 µM Y Inhibited autophagy, decreased the translation of proteins. [ 111 ] Melanoma B16 In vitro 20 μM N Induced lysosomal accumulation and oxidative stress, leading to mitochondrial depolarization and apoptosis.…”

Prognostic value of autophagy-related genes based on single-cell RNA-sequencing in colorectal cancer

“…Chloroquine (CQ) is an autophagy inhibitor that blocks autophagosome-lysosome fusion. In Melanoma, CQ decreases the infiltration of lymphocytes and macrophages in the TME and enhances the anticancer effects of the MEK inhibitor trametinib (TRA) ( Degan et al, 2022 ; Li et al, 2022 ). In present study, we calculated the risk score of patients with CRC based on the expression levels of ARGs and coefficients of Cox regression survival analysis and divided the patients into high- and low-risk groups according to the median of risk score.…”