posted on 2016-04-14, 00:00authored byHongbo Zheng, Yiwen Dong, Lin Li, Bin Sun, Lei Liu, Huiqing Yuan, Hongxiang Lou
Paraptosis is nonapoptotic cell death
characterized by massive
endoplasmic reticulum (ER)- or mitochondria-derived vacuoles. Induction
of paraptosis offers significant advantages for the treatment of chemotherapy-resistant
tumors compared with anticancer drugs that rely on apoptosis. Because
some natural alkaloids induce paraptotic cell death, a novel series
of benzo[a]quinolizidine derivatives were synthesized,
and their antiproliferative activity and ability to induce cytoplasmic
vacuolation were analyzed. Structural optimization led to the identification
of the potent compound 22b, which inhibited cancer cell
proliferation in vitro and in vivo and profoundly facilitated paraptosis-like
cell death and induced caspase-dependent apoptosis. Further investigation
revealed that 22b-mediated vacuolation originated from
persistent ER stress and upregulation of LC3B. Paraptosis induced
by benzo[a]quinolizidine derivatives thus represents
an alternative strategy for cancer chemotherapy.