Discovery of Novel Autophagy Inhibitors and Their Sensitization Abilities for Vincristine‐Resistant Esophageal Cancer Cell Line Eca109/VCR

Abstract

Resistance phenomena, especially acquired drug resistance, have been severely hampering the application of chemotherapeutics during cancer chemotherapy. Autophagy plays a role in maintaining the survival of cancer cells and might mediate resistance to chemotherapy drugs. Herein, a new series of 5‐amino‐2‐ether‐benzamide derivatives were synthesized and evaluated as autophagy inhibitors. Selected from 14 synthesized compounds as lead autophagy inhibitor, N‐(cyclohexylmethyl)‐5‐(((cyclohexylmethyl)amino)methyl)‐2‐((4‐(trifluoromethyl)benzyl)oxy)benzamide (4 d) showed the most obvious effect of LC3B protein conversion. Further, its autophagy inhibition, evaluated by using transmission electron microscopy and confocal microscopy, showed that the fusion of autophagosomes and lysosomes in the final stage of autophagic flux was suppressed. We also found that 4 d could enhance the chemosensitivity of vincristine in vincristine‐resistant esophageal cancer cell line Eca109/VCR in a synergistic, associative manner. Moreover, a computational study showed that 4 d might bind with p62‐zz to inhibit autophagy. We also found 4 d to be relatively less cytotoxic to normal cells versus cancer cells than the reported p62‐zz inhibitor.

Vincristine in Combination Therapy of Cancer: Emerging Trends in Clinics

“…In nephroblastoma cells (G401), a commonly used autophagy inhibitor chloroquine (10 µM) increased the cytotoxicity of vincristine by 15%, when vincristine was administered at low concentrations (1–2 nM) for 24 h [ 184 ]. Similarly, a novel autophagy inhibitor N -(cyclohexylmethyl)-5(((cyclohexylmethyl)amino)methyl)-2-((4-(trifluoromethyl)benzyl)oxy)benzamide reported by Shan et al synergizes with vincristine to enhance cytotoxicity in resistant esophageal cancer cells (Eca109/VCR) [ 185 ]. In general, inhibition of autophagy is beneficial to eliminate cancer cell resistance to vincristine.…”

Nobiletin in Cancer Therapy: How This Plant Derived-Natural Compound Targets Various Oncogene and Onco-Suppressor Pathways

“…However, an interesting point is the induction of autophagy by NOB. It seems that the inhibition of autophagy in cancer cells may enhance the number of cells undergoing apoptosis [228]. In gastric cancer cells exposed to NOB, the inhibition of autophagy elevates the capability of NOB in the stimulation of apoptosis [229].…”

Induction of STK11-dependent cytoprotective autophagy in breast cancer cells upon honokiol treatment

“…Efficacy of autophagy inhibition using FDA-approved chloroquine or hydroxychloroquine in combination with chemotherapy is being investigated in many clinical trials [68][69][70][71][72] . While few FDAapproved autophagy inducers such as chloroquine, hydroxychloroquine, rapamycin and its analogs are being investigated in clinical studies, several new autophagy inhibitors are also being developed and tested namely, 2-amino-nicotinonitrile compound (w09) 73 , 5-amino-2ether-benzamide derivatives 74 , STF-62247, and pimozide 75 . Future studies may show efficacy of these novel autophagy inhibitors in combination with standard anticancer therapeutic regimens.…”