Apoptosis is Induced in Cancer Cells via the Mitochondrial Pathway by the Novel Xylocydine-Derived Compound JRS-15

Abstract

The novel compound JRS-15 was obtained through the chemical modification of xylocydine. JRS-15 exhibited much stronger cytotoxic and pro-apoptotic activity than its parent compound in various cancer cell lines, with IC50 values in HeLa, HepG2, SK-HEP-1, PC-3M and A549 cells ranging from 12.42 to 28.25 μM. In addition, it is more potent for killing cancer than non-cancerous cells. Mechanistic studies showed that JRS-15 treatment arrested cell cycle at the G1/S phase, which further triggered the translocation of Bax and Bak to the mitochondria, resulting in mitochondrial membrane potential (MMP) depolarization and the subsequent release of cytochrome c and the second mitochondria-derived activator of caspase (Smac). The sequential activation of caspase-9 and caspase-3/7 and the cleavage of poly (ADP-ribose) polymerase (PARP) were observed following these mitochondrial events. Caspase-8, an initiator caspase that is required to activate the membrane receptor-mediated extrinsic apoptosis pathway was not activated in JRS-15-treated cells. Further analysis showed that the levels of the anti-apoptotic proteins Bcl-xL and XIAP were significantly reduced upon JRS-15 treatment. Furthermore, the caspase-9 inhibitor z-LEHD-fmk, the pan-caspase inhibitor z-VAD-fmk, and Bcl-xL or XIAP overexpression all effectively prevented JRS-15-induced apoptosis. Taken together, these results indicate that JRS-15 induces cancer cell apoptosis by regulating multiple apoptosis-related proteins, and this compound may therefore be a good candidate reagent for anticancer therapy.

Editorial of the Special Issue: Signaling Molecules and Signal Transduction in Cells

“…Dai et al studied the anti-tumor effect of rapamycin inducing apoptosis and autophagy on pancreatic cancer cells [2]. Sun et al proffer that JRS-15 , a derivative of xylocydine which was a novel cyclin-dependent kinase inhibitor, induced mitochondrial apoptosis in several cancer cell lines [3]. Kalimuthu et al reviewed the effect of various bioactive compounds from marine organisms including sponges, actinomycetes and soft corals on the diverse apoptotic pathways of cancer cells [4].…”

Pyrrolo[2,3‐d]pyrimidine (7‐deazapurine) as a privileged scaffold in design of antitumor and antiviral nucleosides

“…As inhibition of HSP70 in cancer cell lines induces apoptosis, derivative 21b has a potential to possess cytotoxic activity but the data are not yet reported. Xylocydine ( 22a ), also called BMK‐Y101, a sugar‐modified analogue of 8‐bromosangivamycin, is a selective inhibitor of cyclin dependent kinases (CDK1, CDK2, CDK7, and CDK9) which demonstrated its antitumor potential in hepatocellular carcinoma both in vitro and in vivo, while being inactive against cervical, prostate, and hepatic carcinoma or lung adenocarcinoma . Further studies with leukemic HL‐60 cell line showed that xylocydine ( 22a ) induces apoptosis in these cells by CDK1 and CDK4 inhibition and upregulation of protein p16 INK4a , which is a CDK inhibitor .…”

“…Combination of radiotherapy and ibulocydine ( 22b ) treatment showed promising results both in vitro (apoptotic cell death accompanied with activation of caspases, decrease in Bcl‐2/Bax expression, loss of mitochondrial membrane potential, and release of cytochrome c into cytosol) and in vivo (reduced tumor volume in lung cancer xenografts in mice) . Replacement of an 8‐bromine atom of xylocydine ( 22a ) by p‐ tolyl, m‐ or p‐ methoxyphenyl, and m‐ or p‐ bromophenyl groups in compounds 23a led to loss of CDK1 and CDK2 inhibitory activity and also JRS‐15 ( 23b ) with 8‐biphenylyl group is devoid of any CDK inhibiton . However, JRS‐15 ( 23b ) showed cytotoxicity in broader panel of cancer cell lines compared to xylocydine ( 22a ), even though these are only moderate (micromolar) .…”

Manumycin induces apoptosis in prostate cancer cells

“…Mitochondria-mediated apoptosis occurs in response to a wide range of stimuli 12. Activation of procaspase-9 to caspase-9 plays an important role in the execution of the mitochondrial apoptotic pathway 13. Furthermore, the B-cell lymphoma (Bcl)-2 family, including the antiapoptotic members Bcl-2 and Bcl-xL and the proapoptotic members Bax and Bad, is critical in apoptosis regulation 14.…”