ABT-263 induces G1/G0-phase arrest, apoptosis and autophagy in human esophageal cancer cells in vitro

Abstract

Both the anti- and pro-apoptotic members of the Bcl-2 family are regulated by a conserved Bcl-2 homology (BH3) domain. ABT-263 (Navitoclax), a novel BH3 mimetic and orally bioavailable Bcl-2 family inhibitor with high affinity for Bcl-xL, Bcl-2 and Bcl-w has entered clinical trials for cancer treatment. But the anticancer mechanisms of ABT-263 have not been fully elucidated. In this study we investigated the effects of ABT-263 on human esophageal cancer cells in vitro and to explore its anticancer mechanisms. Treatment with ABT-263 dose-dependently suppressed the viability of 3 human esophageal cancer cells with IC values of 10.7±1.4, 7.1±1.5 and 8.2±1.6 μmol/L, in EC109, HKESC-2 and CaES-17 cells, respectively. ABT-263 (5-20 μmol/L) dose-dependently induced G/G-phase arrest in the 3 cancer cell lines and induced apoptosis evidenced by increased the Annexin V-positive cell population and elevated levels of cleaved caspase 3, cleaved caspase 9 and PARP. We further demonstrated that ABT-263 treatment markedly increased the expression of p21 and decreased the expression of cyclin D1 and phospho-Rb (retinoblastoma tumor suppressor protein) (Ser780) proteins that contributed to the G/G-phase arrest. Knockdown of p21 attenuated ABT-263-induced G/G-phase arrest. Moreover, ABT-263 treatment enhanced pro-survival autophagy, shown as the increased LC3-II levels and decreased p62 levels, which counteracted its anticancer activity. Our results suggest that ABT-263 exerts cytostatic and cytotoxic effects on human esophageal cancer cells in vitro and enhances pro-survival autophagy, which counteracts its anticancer activity.

Wee1 Inhibitor AZD1775 Effectively Inhibits the Malignant Phenotypes of Esophageal Squamous Cell Carcinoma In Vitro and In Vivo

“…In addition, AZD1775 sensitizes acute myelogenous leukemia to cytarabine, medulloblastoma cell lines to cisplatin, and high-grade glioma cell lines to irradiation, independently of p53 functionality (Porter et al, 2012; Harris et al, 2014; Mueller et al, 2014). Recently, Hauge S et al reported that the p21 (a downstream target of p53)-deficient cancer cells are more sensitive to AZD1775 alone or in combination with ionizing radiation (Hauge et al, 2019), whereas both cell lines used in this study have been demonstrated to express p21 (Lin et al, 2017; Liu et al, 2018). Collectively, these findings suggest that whether the status of p53 or p21 is predictive of AZD1775 response largely depends on the types of cancer.…”

Plasma dilution improves cognition and attenuates neuroinflammation in old mice

“…ABT 263 (Navitoclax) is a chemotherapy drug that is used to induce apoptosis in cervical, esophageal, leukemia, and lung cancer cells by inhibiting the antiapoptotic proteins, Bcl-2 and Bcl-xL [35][36][37][38]. ABT 263 was shown to selectively clear senescent cells in vivo through inhibition of Bcl proteins [39-41] and to diminish SASP [42].…”

Senolytic compound ABT-263 improved senescent macrophages function by inducing autophagy and protected the aged mouse from sepsis

“…Several studies have verified that ABT-263 can induced autophagy by increasing LC3-II level and suppressing p62 [20]. Although it is known that inhibition of Bcl2 can induce autophagy [21], the mechanism are still controversial.…”