Indomethacin Disrupts Autophagic Flux by Inducing Lysosomal Dysfunction in Gastric Cancer Cells and Increases Their Sensitivity to Cytotoxic Drugs

Abstract

NSAIDs inhibit tumorigenesis in gastrointestinal tissues and have been proposed as coadjuvant agents to chemotherapy. The ability of cancer epithelial cells to adapt to the tumour environment and to resist cytotoxic agents seems to depend on rescue mechanisms such as autophagy. In the present study we aimed to determine whether an NSAID with sensitizing properties such as indomethacin modulates autophagy in gastric cancer epithelial cells. We observed that indomethacin causes lysosomal dysfunction in AGS cells and promotes the accumulation of autophagy substrates without altering mTOR activity. Indomethacin enhanced the inhibitory effects of the lysosomotropic agent chloroquine on lysosome activity and autophagy, but lacked any effect when both functions were maximally reduced with another lysosome inhibitor (bafilomycin B1). Indomethacin, alone and in combination with chloroquine, also hindered the autophagic flux stimulated by the antineoplastic drug oxaliplatin and enhanced its toxic effect, increasing the rate of apoptosis/necrosis and undermining cell viability. In summary, our results indicate that indomethacin disrupts autophagic flux by disturbing the normal functioning of lysosomes and, by doing so, increases the sensitivity of gastric cancer cells to cytotoxic agents, an effect that could be used to overcome cancer cell resistance to antineoplastic regimes.

Dietary Compound Isoliquiritigenin, an Antioxidant from Licorice, Suppresses Triple-Negative Breast Tumor Growth via Apoptotic Death Program Activation in Cell and Xenograft Animal Models

“…In addition, we found that treatment with ISL induced autophagy-associated signaling proteins mTOR and ULK1 were downregulated by ISL treatment, while the expressions of p62, Beclin1, and LC3 autophagy-promoting proteins were all increased. However, during autophagy progression, p62 was enclosed by autolysosome and degraded by cathepsin B in lysosomes [44], although both p62 and LC3 II levels were increased by ISL. Therefore, ISL influences p62 accumulation by reduced cathepsin B to inhibit autophagy by blocked phagolysosome formation.…”

p62 aggregates mediated Caspase 8 activation is responsible for progression of ovarian cancer

“…During this process p62 binds ubiquitinated proteins through its ubiquitin‐associated (UBA) domain and anchors to LC3 in the autophagosome membrane through its LC3‐interacting region (LIR) domain . Recent evidence suggests that the completion of autophagy relies on smooth autophagic flux and renewal of autophagosomes whereas dysfunction in the autophagy pathway leads to the accumulation of p62 and damaged proteins that possibly results in cell death …”

Hydroxychloroquine induced lung cancer suppression by enhancing chemo-sensitization and promoting the transition of M2-TAMs to M1-like macrophages

“…In addition to target cancer cells directly, applying specific agents that induce host immune defences to suppress tumour growth may improve therapeutic outcomes. Recently, lysosome-associated agents, such as chloroquine (CQ), have been implicated as chemo-sensitizers [ 10 , 11 ]. In fact, several clinical trials have evaluated the ability of CQ to enhance the efficacy of chemotherapy in a variety of cancer treatments (NCT00969306, NCT02432417) [ 12 – 14 ].…”