ABSTRACT
To overcome the poor prognosis of patients with ovarian cancer, attempting to target ovarian cancer with effective antitumor compounds has been conducted for numerous years. Although the 3,4dihydroquinazoline derivative KYS05090S was known to exert antitumor effects in A549 and ovarian cancer cells by inhibition of Ttype Ca2+ channels, the complete underlying antitumor mechanism of this compound remains unclear. Thus, in the present study, the potential apoptotic mechanism of KYS05090S was elucidated in SKOV3 and OVCAR3 ovarian cancer cells. KYS05090S exerted significant cytotoxicity in SKOV3 and OVCAR3 ovarian cancer cells, and also increased the number of apoptotic bodies, and the number of terminal deoxynucleotidyl transferase dUTP nick end labeling positive cells and the subG1 population as a feature of apoptosis. Consistently, KYS05090S induced cleavage of poly(ADPribose) polymerase and caspase9/3 in ovarian cancer cells. Notably, KYS05090S attenuated the expression of antiapoptotic proteins, including cyclin D1 and Bcell lymphoma2 (Bcl2), and reduced the phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) in ovarian cancer cells. Additionally, KYS05090S blocked the nuclear translocation of STAT3 and suppressed the signaling of JAK2/STAT3 in interleukin6treated SKOV3 cells, as a STAT3 activator. Overall, these observations indicated that inhibition of JAK2/STAT3 signaling and activation of caspase9/3 are critically involved in the effects of KYS05090S on apoptosis in ovarian cancer types, and the compound may be beneficial as a potent antitumor agent.
Subject(s)
Caspases/metabolism , Janus Kinase 2/metabolism , Ovarian Neoplasms/metabolism , Quinazolines/pharmacology , STAT3 Transcription Factor/metabolism , A549 Cells , Caspase 3/metabolism , Caspase 9/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Female , Humans , Ovarian Neoplasms/drug therapy , Phosphorylation/drug effects , Protein Transport/drug effects , Signal Transduction/drug effectsABSTRACT
Although auraptene, a prenyloxy coumarin from Citrus species, was known to have anti-oxidant, anti-bacterial, antiinflammatory, and anti-tumor activities, the underlying anti-tumor mechanism of auraptene in prostate cancers is not fully understood to date. Thus, in the present study, we have investigated the anti-tumor mechanism of auraptene mainly in PC3 and DU145 prostate cancer cells, because auraptene suppressed the viability of androgen-independent PC3 and DU145 prostate cancer cells better than androgen-sensitive LNCaP cells. Also, auraptene notably increased sub-G1 cell population and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells as features of apoptosis in two prostate cancer cells compared with untreated control. Consistently, auraptene cleaved poly(ADP-ribose) polymerase, activated caspase-9 and caspase-3, suppressed the expression of anti-apoptotic proteins, including Bcl-2 and myeloid cell leukemia 1 (Mcl-1), and also activated pro-apoptotic protein Bax in both prostate cancer cells. However, Mcl-1 overexpression reversed the apoptotic effect of auraptene to increase sub-G1 population and induce caspase-9/3 in both prostate cancer cells. Taken together, the results support scientific evidences that auraptene induces apoptosis in PC3 and DU145 prostate cancer cells via Mcl-1-mediated activation of caspases as a potent chemopreventive agent for prostate cancer prevention and treatment. Copyright © 2017 John Wiley & Sons, Ltd.
Subject(s)
Apoptosis/drug effects , Caspase 3/metabolism , Caspase 9/metabolism , Coumarins/pharmacology , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Prostatic Neoplasms/pathology , Cell Line, Tumor , Humans , Male , Poly(ADP-ribose) Polymerases/metabolism , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , bcl-2-Associated X Protein/metabolismABSTRACT
In the present study, the underlying apoptotic mechanism of sanggenol L was elucidated in ovarian cancer cells. Sanggenol L showed cytotoxic and antiproliferative effect in A2780, SKOV-3, and OVCAR-3 ovarian cancer cells in a concentration-dependent fashion. Consistently, sanggenol L increased sub-G1 phase population and early and late apoptotic portion in ovarian cancer cells. Also, sanggenol L activated caspase9/3, suppressed the phosphorylation of IκBα and p65 NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), attenuated the expression of Cyclin D1, and cleaved poly(adenosine diphosphate ribose -ribose) polymerase in SKOV-3, A2780, and OVCAR-3 cells. Furthermore, sanggenol L blocked nuclear translocation of NF-κB and also attenuated the expression of NF-κB related genes such as c-Myc, Cyclin D1, and Bcl-X L, Bcl-2, in lipopolysaccharide-treated SKOV-3 cells. Overall, our findings for the first time suggest that sanggenol L induces apoptosis via caspase activation and inhibition of NF-κB/IκBα phosphorylation as a potent chemotherapeutic agent for ovarian cancers.