Autophagy inhibitors for resistant cancers

Autophagy is a process by which cells that are under stress and deprived of nutrients pause to recycle themselves in order to maintain viability.  Autophagosomes comprised of cellular organelles are formed, followed by Lysosomal destruction; the cell then uses the substrates for synthesis and reconstitution.  Cells in autophagy do not replicate…

Cancer cells frequently invoke autophagy programs as a respite to conserve energy and resources until conditions favorable for replication are restored.  Hence, autophagy is cytoprotective.

Autophagy has also been observed in cancer cells as a mechanism of chemotherapy resistance.  This study by Chittarajan et al., sought to evaluate autophagy inhibition in triple negative breast cancer models.  TNBC is characterized by lack of receptors for estrogen, progesterone, and HER-2/neu.  Most patients with TNBC develop chemotherapy resistance.

Hydroxychloroquine causes lysosomal acidification and inhibition of fusion of autophagosomes with lysosomes, which causes the accumulation of autophagosomes and rapid cell death.  (see Liu et al – hydroxychloroquine ol_7_4_1057_PDF (1).)  The authors demonstrated a significant reduction in growth of epirubicin resistant TNBC with a combination of hydroxychloroquine and epirubicin – Autophagy Clin Cancer Res-2014-Chittaranjan-3159-73.

The results of this experiment suggest that autophagy inhibitors combined with chemotherapy in patients with chemo-resistant TNBC is a rational clinical strategy.

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