GL0388 Activates Bax and Induce Bax-Mediated Apoptosis
Posted On 2021-07-14
Bax is a member of the bcl-2 gene family. Specifically, BCL2 family members are relevant to a variety of anti-apoptotic or pro-apoptotic regulators. The expression of this gene is regulated by the tumor suppressor gene p53. Besides, Bax interacts with mitochondrial voltage-dependent anion channel VDAC and induces its opening. Moreover, Bax protein plays an important role in apoptosis by forming pores in the outer membrane of mitochondria.
Furthermore, members of the Bax protein family are activated in various ways. For example, cleavage of caspase, inhibition of protein kinase and/or activation of phosphatase, and increase of intracellular pH can activate it. Under normal conditions, Bax is in the cytoplasm mainly through continuous reverse translocation from mitochondria. Under apoptotic conditions, activated Bax and Bak are accumulating at mom. Meanwhile, they oligomerize and mediate MOMP, leading to the release of Pro-apoptotic factors such as Cytochrome c. Nonetheless, Bax plays a key role in regulating mitochondrial dysfunction and controlling apoptosis of normal and cancer cells. Here, we will introduce a Bax activator, GL0388.
GL0388 Activates Bax and Induces Bax-Mediated Apoptosis.
Firstly, GL0388 is a Bax activator that results in Bax insertion into the mitochondrial membrane. Interestingly, GL0388 shows antiproliferative activities against various cancer cells, with IC50s of 0.299-1.57 μM. GL0388 activates Bax and induces Bax-mediated apoptosis. Interestingly, GL0388 suppresses breast cancer xenograft tumor growth in vivo.
Secondly, GL0388 with 0.1-10 μM for 72 h inhibits the cell proliferation of MDA-MB-231 and MCF-7 breast cancer cell lines. Particularly, GL0388 has IC50s of 0.96 μM and 0.52 μM, respectively. GL0388 inhibits cell proliferation in 60 human tumor cell lines, with GI550s of 0.299-1.57 μM. Obviously, GL0388 significantly upregulates the cleaved PARP-1 and cleaved caspase 3 in MDA-MB-231 cells. GL0388 inhibits the colony formation and invasion of breast cancer cells. By the way, GL0388 promotes Bax insertion into mitochondrial membranes of MDA-MB-231 cells in a dose-dependent manner. Additionally, GL0388 increases cytochrome c in the cytosolic fraction of MDA-MB-231 cells.
Last but not least, GL0388 with 10-20 mg/kg by i.p. dose-dependently suppresses the growth of MDA-MB-231 tumors in mice.
All in all, GL0388 activates Bax and induces Bax-mediated apoptosis.
Liu G, et, al. Eur J Med Chem. 2021 Jul 5;219:113427.