Abstract
Epithelial ovarian cancer is most lethal in female reproductive carcinomas owing to the high chemoresistance and metastasis, so more efficient therapeutic agents are terribly needed. A propadiene compound: 1-phenylpropadienyl phosphine oxide (PHPO), was employed to test the chemotherapeutic efficacy against ovarian cancer cell lines. MTT assay showed that PHPO displayed a much lower IC50 than cisplatin and paclitaxel, while combination treatment of cells with PHPO + cisplatin induced more apoptosis than with PHPO + paclitaxel or with cisplatin + paclitaxel (p < 0.05). Animal assays demonstrated that subcutaneous tumor growth was highly inhibited by PHPO + cisplatin, compared with that inhibited by PHPO or by cisplatin treatment alone, indicating PHPO and cisplatin may have synergistic effects against ovarian cancer growth. We also found that PHPO induced few side effects on animals, compared with cisplatin. Mechanistic studies suggested that treatment of cells with PHPO or with PHPO + cisplatin differentially inhibited the PI3K/Akt, MAPK and ATM/Chk2 pathways, which consequently suppressed the anti-apoptotic factors Bcl-xL, Bcl-2 and XIAP, but activated the pro-apoptotic factors Bad, Bax, p53, caspase 9, caspase 8, caspase 7 and PARP. Taken together, PHPO may induce cell apoptosis through multiple signal pathways, especially when used along with cisplatin. Therefore, PHPO may be explored as a prospective agent to effectively treat ovarian cancer.
Highlights
Epithelial ovarian cancer (EOC) accounts for only 4% of cancer deaths in women, but is most lethal in female reproductive carcinomas mainly due to the late diagnosis and peritoneal dissemination [1, 2]
Epithelial ovarian cancer is most lethal in female reproductive carcinomas owing to the high chemoresistance and metastasis, so more efficient therapeutic agents are terribly needed
Cells were treated with different concentrations of phosphine oxide (PHPO), cisplatin or paclitaxel for 48 hours, and the cell viability was ascertained by MTT assay
Summary
Epithelial ovarian cancer (EOC) accounts for only 4% of cancer deaths in women, but is most lethal in female reproductive carcinomas mainly due to the late diagnosis and peritoneal dissemination [1, 2]. The PI3K/Akt signaling is commonly activated and plays an important role in cancer cell proliferation, metastasis and chemoresistance [5, 6]. Amplification or mutations of PIK3CA (encoding the catalytic subunit of PI3K-p110α) and the phosphorylation of Akt can activate this pathway in roughly 70% of ovarian cancer [7]. In the PI3K/Akt pathway, PI3K initiates the survival mechanism through Akt that exerts anti-apoptotic effects, antagonizes www.impactjournals.com/oncotarget cell cycle arrest and evokes chemoresistance via mTOR signaling [8, 9]. The phosphorylated Akt activates the anti-apoptotic Bcl-2 family members (Bcl-xL, Bcl-2, Mcl-1, Bcl-w and A1), blocks the functions of the pro-apoptotic factors (Bak, Bad and Bax), and alters the activity of caspase-processing, leading to chemoresistance [8, 11]. XIAP promotes cell survival though preserving the integrity and function of PI3K/Akt pathway [14]
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