Targeting the Retinoic Acid Pathway to Eradicate Cancer Stem Cells

All-trans retinoic acid is a morphogen during embryogenesis and a teratogen. Cancer is an error of development, and the retinoic acid receptors (RAR) for all-trans retinoic acid play a role in cancer. Expression of the cytosolic aldehyde dehydrogenases, which mediate the last step to the synthesis of all-trans retinoic acid, is deregulated in various human cancers. Inhibiting these enzymes using a variety of agents reduced the proliferation of lung cancer cells, reduced the proliferation and induced apoptosis of ovarian, prostate, squamous, and uterine cancer cells, and sensitised breast, colorectal and ovarian cancer cells to chemotherapeutic agents. RAR gamma is an oncogene within some cases of AML, cholangiocarcinoma, colorectal cancer, clear cell renal cell carcinoma, hepatocellular carcinoma, pancreatic ductal adenocarcinoma, prostate cancer, and ovarian cancer. Pan-RAR and RAR gamma antagonist inhibition of the action of RAR gamma led to necroptosis of human prostate and pediatric brain tumour cancer stem cells. Treatment of hepatocellular carcinoma cells with the flavenoid acacetin, which interferes with the action of RAR gamma, decreased cell growth and induced apoptosis. Targeting the retinoic acid pathway is promising regarding the development of new drugs to eradicate cancer stem cells.

Automated summary

All-trans retinoic acid plays a role in embryogenesis and also acts as a teratogen. The deregulation of cytosolic aldehyde dehydrogenases in various human cancers affects the synthesis of all-trans retinoic acid. Inhibiting these enzymes reduces cancer cell proliferation, induces apoptosis, and enhances chemotherapeutic sensitivity. RAR gamma is an oncogene in several types of cancer, and inhibiting its action leads to cancer cell death. Targeting the retinoic acid pathway shows promise in eliminating cancer stem cells.