Autophagy in Cancer: Regulation by Small Molecules

Limpert, Allison S.; Lambert, Lester J.; Bakas, Nicole A.; Bata, Nicole; Brun, Sonja N.; Shaw, Reuben J.; Cosford, Nicholas D. P.

doi:10.1016/j.tips.2018.10.004

Cited by 92 publications

(59 citation statements)

References 78 publications

(83 reference statements)

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“…In addition, MRT68921 treated cells show significant increase in SQSTM1 level and decrease in LC3-2/LC3-1 ratio. These results suggested that MRT68921 treatment efficiently inhibits ULK-mediated autophagy [77] . However, the molecular basis of this block remains to be elucidated.…”

Section: Unc-51-like Kinases Inhibitorsmentioning

confidence: 75%

Targeting autophagy with small molecules for cancer therapy

Kondapuram¹,

Sarvagalla²,

Coumar³

2019

JCMT

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Autophagy is a conserved lysosomal-dependent catabolic process that maintains the cellular homeostasis by recycling misfolded proteins and damaged organelles. It involves a series of ordered events (initiation, nucleation, elongation, lysosomal fusion and degradation) that are tightly regulated/controlled by diverse cell signals and stress. It is like a double-edged sword that can play either a protective or destructive role in cancer, by pro-survival or apoptotic cues. Recently, modulating autophagy by pharmacological agents has become an attractive strategy to treat cancer. Currently, a number of small molecules that inhibit autophagy initiation (e.g., ULK kinase inhibitors), nucleation (e.g., Vps34 inhibitors), elongation (e.g., ATG4 inhibitors) and lysosome fusion (e.g., chloroquine, hydroxyl chloroquine, etc .) are reported in pre-clinical and clinical study. Also a number of small molecules reported to induce autophagy by targeting mammalian target of rapamycin (e.g., rapamycin analogs) or adenosine 5'-monophosphateactivated protein kinase (e.g., sulforaphane). The study results suggest that many potential "druggable" targets exist in the autophagy pathway that could be harnessed for developing new cancer therapeutics. In this review, we discuss the reported autophagy modulators (inhibitors and inducers), their molecular mode of action and their applications in cancer therapy.

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Section: Unc-51-like Kinases Inhibitorsmentioning

confidence: 75%

Targeting autophagy with small molecules for cancer therapy

Kondapuram¹,

Sarvagalla²,

Coumar³

2019

JCMT

View full text Add to dashboard Cite

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“…CQ and its analog, hydroxychloroquine (HCQ), are the only autophagy inhibitor being used for treating cancer in clinical trials 33 . However, Phase I/II clinical trials with CQ and HCQ showed mixed results with varying levels of efficacy, highlighting the needs to develop alternative autophagy inhibitors [33][34][35] . Numerous studies have indicated that GLP inhibits tumorigenesis through inducing apoptosis, inhibiting invasion, and regulating immune response 3,5,8 .…”

Section: Discussionmentioning

confidence: 99%

Autophagic flux disruption contributes to Ganoderma lucidum polysaccharide-induced apoptosis in human colorectal cancer cells via MAPK/ERK activation

et al. 2019

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Targeting autophagy may serve as a promising strategy for cancer therapy. Ganoderma lucidum polysaccharide (GLP) has been shown to exert promising anti-cancer effects. However, the underlying mechanisms remain elusive. Whether GLP regulates autophagy in cancer has never been reported. In this study, GLP induced the initiation of autophagy in colorectal cancer (CRC) HT-29 and HCT116 cells, as evidenced by enhanced level of LC3-II protein, GFP-LC3 puncta, and increased formation of double membrane vacuoles. However, GLP treatment caused marked increase of p62 expression. Addition of late stage autophagy inhibitor, chloroquine (CQ), further enhanced LC3-II and p62 level, as well as increased autophagosome accumulation, suggesting a blockage of autophagic flux by GLP in CRC cells. We then found GLP blocked autophagosome and lysosome fusion as determined by mRFP-GFP-LC3 colocalization analysis. Mechanistic study revealed that GLP-induced disruption of autophagosome-lysosome fusion is due to reduced lysosome acidification and lysosomal cathepsin activities. Cell viability and flow cytometry assays revealed that GLPinduced autophagosome accumulation is responsible for GLP-induced apoptosis in CRC cells. In line with this, inhibition of autophagy initiation by 3-methyladenine (3-MA), an early stage autophagy inhibitor, attenuated GLPinduced apoptosis. In contrast, suppression of autophagy at late stage by CQ enhanced the anti-cancer effect of GLP. Furthermore, we demonstrated that GLP-induced autophagosome accumulation and apoptosis is mediated via MAPK/ERK activation. Finally, GLP inhibited tumor growth and also inhibited autophagic flux in vivo. These results unveil new molecular mechanism underlying anti-cancer effects of GLP, suggesting that GLP is a potent autophagy inhibitor and might be useful in anticancer therapy.

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“…For example, it is not clear to what extent lysosome regulation per se contributes to the tumorigenic role of AMPK in vivo. Genetic or pharmacologic inhibition of lysosomal function could help address this issue (Limpert et al, 2018). Furthermore, what might be the relevant outputs of lysosomal function in this context?…”

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confidence: 99%