Selective Termination of Autophagy-Dependent Cancers
Abstract
:1. What Is Autophagy Dependence?
2. What Makes Autophagy-Dependent Cancer Cells PIKFYVE-Dependent?
3. The Role of PIKFYVE in Lysosome Homeostasis and Autophagy
4. Current Strategies for Selectively Inhibiting PIKFYVE Activity
- (a)
- Identify small molecules that inhibit PIKFYVE activity
- (b)
- Identify small molecules that inhibit either VAC14 or FIG4
- (c)
- Target the PIKFYVE protein for degradation
5. PIKFYVE Inhibitors Have Both Primary and Secondary Targets
6. The Significance of Secondary Targets
7. The Effects of PIKFYVE Inhibitors in Immunotherapy
- (a)
- PIKFYVE suppresses the antigen presenting potential of innate immune cells.
- (b)
- PIKFYVE inhibitors facilitate the innate immune response against cancer
8. The Efficacy of PIKFYVE Inhibitors In Vitro
9. The Efficacy of PIKFYVE Inhibitors In Vivo
10. Inhibiting Cell Proliferation Precedes Inducing Cell Death
11. PIKFYVE Inhibitors Induce PERK-Dependent Endoplasmic Reticulum Stress
12. PIKFYVE Inhibitors Induce Non-Canonical Apoptosis
13. Therapeutic Potential of PIKFYVE Inhibitors against Cancers
14. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Group | Inhibitor | Selection | Targets | |
---|---|---|---|---|
Primary | Secondary | |||
Kd (nM) | ||||
A | WX8 | induce excess DNA replication | PIKFYVE 0.9 | PIP4K2C 340 |
XB6 | PIKFYVE 11 | PIP4K2C 990 | ||
XBA | PIKFYVE 16 | PIP4K2C 20,000 | ||
Vacuolin-1 | increase LC3 protein | PIKFYVE 39 | ||
B | apilimod | reduce cell proliferation | PIKFYVE 0.075, 5.3, 65 | VAC14 |
APY0201 | inhibit PIK3CA | PIKFYVE | PIK3CA PIK3CB PIK3CD | |
NDF | excess DNA replication | PIKFYVE 1.6 | PIP4K2C 24,000 | |
WWL | PIKFYVE 4.8 | PIP4K2C 9200 | ||
C | YM201636 | inhibit PIK3CA | PIKFYVE 9 | PIK3CA PIK3CB PIK3CD |
PI-103 | ||||
D | ESK981 | inhibit receptor tyrosine kinases | PIKFYVE 12 | PIP5K1A 230 PIP5K1C 210 |
HZX-02-059 | cytoplasmic vacuolization & cell death | PIKFYVE 10 * | PIP4K2C | |
L22 | PIKFYVE 0.47 | |||
SB202190 SB203580 | inhibit p38MAPK | p38MAPK | PIKFYVE |
Inhibitor | Median IC50 ( µM) | Reference | |||
---|---|---|---|---|---|
Cancer Cells | Normal Cells | ||||
WX8 | 7 different cancers | 0.34 | 4 different | 21 | [27] |
10 melanomas | 2.8 | ||||
12 different cancers | 0.24 | 8 different | 2.8 | [7] | |
apilimod | 48 lymphomas | 0.13 | 12 different | 15 | [6] |
11 Burkitt’s lymphomas | 0.15 | ||||
APY0201 | 5 gastric cancers | 0.1–1 | [52] | ||
YM201636 | 2 hepatocellular carcinomas | 1–5 | [93] | ||
ESK981 | 7 prostates | 0.08 | [9] | ||
SB202190 | 12 different cancers | 4.4 | 8 different | 23 | [7] |
recombinant PIKFYVE protein | 0.4 * | [34] | |||
1 prostate | 12.2 ** | ||||
HZX-02-059 | 3 lymphomas | 0.19 | [55] | ||
L22 | 1 breast | 0.23 | [56] |
Inhibitor | Cancer | Tumor | Reference |
---|---|---|---|
WX8 | melanoma | xenografts | [27] |
embryonal carcinoma | ex vivo xenografts | [8] | |
WX8 ± SB202190 | colon adenocarcinoma | xenografts | [7] |
vacuolin-1 | melanoma breast | transgenic mouse models | [60] |
apilimod | lymphoma | xenografts | [6] |
APY0201 | gastric | xenografts | [52] |
APY0201 apilimod YM201636 | multiple myeloma | ex vivo | [29] |
YM201636 | hepatocellular carcinoma | xenografts | [93] |
ESK981 | prostate | ex vivo xenografts | [9] |
HZX-02-059 | lymphoma | xenografts | [55] |
L22 | breast | xenografts | [56] |
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Roy, A.; DePamphilis, M.L. Selective Termination of Autophagy-Dependent Cancers. Cells 2024, 13, 1096. https://doi.org/10.3390/cells13131096
Roy A, DePamphilis ML. Selective Termination of Autophagy-Dependent Cancers. Cells. 2024; 13(13):1096. https://doi.org/10.3390/cells13131096
Chicago/Turabian StyleRoy, Ajit, and Melvin L. DePamphilis. 2024. "Selective Termination of Autophagy-Dependent Cancers" Cells 13, no. 13: 1096. https://doi.org/10.3390/cells13131096
APA StyleRoy, A., & DePamphilis, M. L. (2024). Selective Termination of Autophagy-Dependent Cancers. Cells, 13(13), 1096. https://doi.org/10.3390/cells13131096