Vorinostat-induced autophagy switches from a death-promoting to a cytoprotective signal to drive acquired resistance

Abstract

Histone deacetylase inhibitors (HDACi) have shown promising activity against hematological malignancies in clinical trials and have led to the approval of vorinostat for the treatment of cutaneous T-cell lymphoma. However, de novo or acquired resistance to HDACi therapy is inevitable, and their molecular mechanisms are still unclear. To gain insight into HDACi resistance, we developed vorinostat-resistant clones from the hematological cell lines U937 and SUDHL6. Although cross-resistant to some but not all HDACi, the resistant cell lines exhibit dramatically increased sensitivity toward chloroquine, an inhibitor of autophagy. Consistent with this, resistant cells growing in vorinostat show increased autophagy. Inhibition of autophagy in vorinostat-resistant U937 cells by knockdown of Beclin-1 or Lamp-2 (lysosome-associated membrane protein 2) restores sensitivity to vorinostat. Interestingly, autophagy is also activated in parental U937 cells by de novo treatment with vorinostat. However, in contrast to the resistant cells, inhibition of autophagy decreases sensitivity to vorinostat. These results indicate that autophagy can switch from a proapoptotic signal to a prosurvival function driving acquired resistance. Moreover, inducers of autophagy (such as mammalian target of rapamycin inhibitors) synergize with vorinostat to induce cell death in parental cells, whereas the resistant cells remain insensitive. These data highlight the complexity of the design of combination strategies using modulators of autophagy and HDACi for the treatment of hematological malignancies.

Inhibition of Akt Reverses the Acquired Resistance to Sorafenib by Switching Protective Autophagy to Autophagic Cell Death in Hepatocellular Carcinoma

“…Here, we have demonstrated that sorafenib at 10 mmol/L activated autophagy, which played a protective role against cell death of parental HCC cells, and is in agreement with a previous report (21); but exhibited a death-promoting role in sorafenib-resistant HCC cells. Autophagy induced by vorinostat, a histone deacetylase inhibitor that has been approved for treating cutaneous T-cell lymphoma in clinic (41), protected against cell death independent of mTOR in vorinostat-resistant lymphoma cells (42). The autophagic pathway crosstalks with both the caspase-dependent and -independent apoptotic pathways (13,21,43).…”

Therapeutic targeting of autophagy in cancer. Part II: Pharmacological modulation of treatment-induced autophagy

“…Treatment with vorinostat also reduces tamoxifen-resistance [85]. Vorinostat-resistant clones of malignant haematological cells show increased basal autophagy levels and are sensitive to chloroquine [86]. Chloroquine even restores vorinostat sensitivity.…”

Synergy between histone deacetylase inhibitors and DNA-damaging agents is mediated by histone deacetylase 2 in colorectal cancer

“…Many HDACi / DNA damaging agent combination strategies are both effective and synergistic whereas others are ineffective or antagonistic with unclear mechanistic reasons for these effects [17]. Hence, understanding the mechanisms of HDACi resistance is crucial to develop more effective combination strategies for the future [18]. …”