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Chloroquine (and its analogue hydroxychloroquine)
Hydroxychloroquine (more commonly used because of its safety profile)
Chloroquine originates from synthetic modifications of quinoline derivatives (it has roots in natural alkaloids like quinine) and is now produced through chemical synthesis. Its repurposing in cancer therapy centers on its ability to disrupt autophagy and lysosomal function, modulate the immune response within the tumor microenvironment, and sensitize cancer cells to chemo- and radiotherapy.
Chloroquine is a synthetic derivative belonging to the 4-aminoquinoline class. It was initially developed in the 1930s from quinoline scaffolds, which themselves are derived from naturally occurring alkaloids like quinine (isolated from the bark of the cinchona tree). Unlike natural products that are directly extracted, chloroquine is produced by chemical synthesis in pharmaceutical laboratories.
Pathways:
-Autophagy Inhibition: By raising intralysosomal pH, chloroquine impairs the fusion of autophagosomes with lysosomes, thereby blocking autophagic flux. This inhibition can sensitize tumor cells to chemotherapy and enhance cell death.
-Lysosomal Dysfunction: Chloroquine accumulates in lysosomes, altering their function. This can lead to lysosomal membrane permeabilization and subsequent activation of cell death pathways.
-Stress-Related Signaling: Chloroquine-induced disruption of autophagy can lead to the accumulation of damaged proteins and organelles, triggering stress responses such as the unfolded protein response (UPR) and reactive oxygen species (ROS) generation.
-TLR (Toll-Like Receptor) Signaling: There is evidence suggesting that chloroquine can inhibit TLR9 signaling
Chemo- and Radiosensitization:
-One of the promising uses of chloroquine in oncology is as an adjuvant to standard therapies.
-By disrupting autophagy—a mechanism that many cancer cells use to survive after treatment—chloroquine can enhance the cytotoxic effects of chemotherapy and radiation.
Hydroxychloroquine (more commonly used because of its safety profile) have used doses ranging from 400 mg per day up to 1200 mg per day in divided doses.
Chloroquine effectiveness is pH sensitive: CQ concentrations in the whole-cell lysate were 7-fold lower at pH 6.8 as compared with pH 7.4