Autophagy (autophagocytosis) is the natural, conserved degradation of the cell. It removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. It allows the orderly degradation and recycling of cellular components. Initially characterized as a primordial degradation pathway induced to protect against starvation. But it has become increasingly clear that autophagy also plays a major role in the homeostasis of non-starved cells. Defects in autophagy have been linked to various human diseases, including neurodegeneration and cancer. So interest in modulating autophagy as a potential treatment for these diseases has grown rapidly.
PHY34 is an ATP6V0A2/CAS Inhibitor Useful in Ovarian Cancer Research.
PHY34 is an inhibitor that inhibits ATP6V0A2 and CAS thereby inhibiting autophagy, and has a nanomolar effect. What’s more, it inhibits cancer cell growth by inducing apoptosis and inhibits tumor growth in xenograft models. Therefore, it can be used for research on high grade serous ovarian cancer.
In vitro, PHY34 (0.001 nM-50 μM, 72 h) inhibits various cancer cells growth with nanomolar potency through activation of apoptosis based on enhanced cPARP levels and has the highest potency in HGSOC cell lines. Morever, PHY34 (100 nM; 24 h) blocks the final breakdown of the autolysosomes in OVCAR8 at 100 nM. And it has the same effect in OVCAR3 at 1 μM. Not only PHY34 (10 nM, 24 h) inhibits the late-stage autophagy that precedes apoptosis induction in OVCAR8, but also PHY34 (100 nM, 48 h) inhibits the late-stage autophagy that precedes apoptosis induction in OVCAR3. In addition, PHY34 (0.01 nM-2 μM, 72 h) induces cell death in the presence of wild-type V0A2, but not V823I mutants in H4 cell. And, PHY34 (10, 100 nM; 48 h, 72 h) changes subcellular localization of nuclear multiple proteins. PHY34 (20 μM, 1 h) binds specificity with ATP6V0A2 subunit. In vivo, PHY34 (0.75 mg/kg, i.p., 3 times a week for 3 weeks) inhibits tumor growth and reduces Ki67 expression in tumor tissue in a female nude mouse tumor bearing model constructed by OVCAR8.
In conclusion, PHY34 is an autophagy inhibitor and can be used for research on ovarian cancer.
Reference
[1]. Mol Cancer Ther. 2018 Oct;17(10):2123-213.
[2]. Cell Death Dis. 2022 Jan 10;13(1):45.