Protoapigenone, a novel flavonoid, inhibits ovarian cancer cell growth in vitro and in vivo

Chang, Hsueh Ling; Su, Jui Hsin; Yeh, Yao Tsung; Lee, Yi Chen; Chen, Huey May; Wu, Yang Chang; Yuan, Shyng‐Shiou F.

doi:10.1016/j.canlet.2008.03.007

Cited by 52 publications

(48 citation statements)

References 26 publications

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“…However, phosphorylation of the p53 Ser 15 residue did not contribute to this WYC02-induced p53 protein accumulation, suggesting that WYC02 does not directly damage DNA because DNA damage normally stimulates ATM/ATR-dependent p53 Ser 15 phosphorylation. Our result is similar to previous reports that p38 MAPK is activated by WYC02 (19,21,22), as its downstream target MAPKAPK2 was found to be phosphorylated starting as early as 2 hours after WYC02 exposure (Fig. 1C).…”

Section: Wyc02 Induces Chromosomal Aberrations But Does Not Produce Msupporting

confidence: 82%

“…1A) were shown to induce oxidative stress, consequently activating the p38 and c-jun-NH 2 -kinase (JNK) 1/2 mitogen-activated protein kinase (MAPK) pathways following cell-cycle arrest and apoptosis in several cancer cell types. These compounds were also found to reduce the size of tumor xenografts in nude mice without exerting toxic effects on the recipient (18)(19)(20)(21)(22). Recently, WYCs were found to induce chromosomal breakage through oxidative stress (18,20), implicating a role for WYCs in interfering with DNA metabolism.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of ATR-Dependent Signaling by Protoapigenone and Its Derivative Sensitizes Cancer Cells to Interstrand Cross-link–Generating Agents In Vitro and In Vivo

Wang

Lee

Chou

et al. 2012

Molecular Cancer Therapeutics

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DNA damage caused during cancer treatment can rapidly activate the ataxia telangiectasia-mutated (ATM) and ATM and Rad3-related (ATR)-dependent phosphorylation of Chk2 and Chk1 kinases, which are hallmarks of the DNA damage response (DDR). Pharmacologic inhibition of ATR causes a synthetic lethal effect on ATMor p53-defective cancers, suggesting that such inhibition is an effective way to improve the sensitivity of cancers to DNA-damaging agents. Here, both the natural compound protoapigenone (WYC02) and its synthetic derivative WYC0209 exhibited cytotoxic effects on various cancer cell lines. WYC02 causes chromosomal aberration in the mitotic spreads of Chinese hamster ovary cells. Interestingly, cancer cells did not exhibit typical DDR markers upon exposure to WYC02 and WYC0209 (WYCs). Further investigation into the molecular mechanisms of WYCs function revealed that they have a potential ability to inhibit DDR, particularly on activation of Chk1 and Fanconi anemia group D2 protein (FANCD2), but not Chk2. In this way, WYCs inhibited ATR-mediated DNA damage checkpoint and repair. Furthermore, when combined with the DNA cross-linking agent cisplatin, treatment with WYCs resulted in increased tumor sensitivity to interstrand crosslink-generating agents both in vitro and in vivo. Our results therefore especially implicate WYCs in enhancing tumor chemosensitivity when the ATR checkpoint is constitutively active in states of oncogene-driven replicative stress or tolerance to DNA-interfering agents.

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Section: Wyc02 Induces Chromosomal Aberrations But Does Not Produce Msupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Inhibition of ATR-Dependent Signaling by Protoapigenone and Its Derivative Sensitizes Cancer Cells to Interstrand Cross-link–Generating Agents In Vitro and In Vivo

Wang

Lee

Chou

et al. 2012

Molecular Cancer Therapeutics

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“…Likewise, several in vivo experiments confirmed the antitumor activity of compounds 1 and/or 2. In nude mice, 1 inhibited the growth of ovarian (MDAH-2774) and prostate (LNCap) cancer xenografts [33,34], while both compounds exerted such activity against cervical (HeLa) cancer xenografts [35,36]. Compound 2 was active against colorectal (HCT116) cancer xenografts in nude mice [28], and it was able to chemosensitize MDA-MB-231 breast cancer xenografts toward cisplatin possibly via the inhibition of DNA repair [10].…”

Section: Discussionmentioning

confidence: 97%

Lower antioxidative capacity of multidrug-resistant cancer cells confers collateral sensitivity to protoflavone derivatives

Stanković

Dankó

Martins

et al. 2015

Cancer Chemother Pharmacol

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“…Follow-up studies showed that protoapigenone decreased the viability of cancer cells through induction of cell cycle arrest and apoptosis [10,11]. In a nude mouse xenograft model, protoapigenone also exhibited significant antitumor activity against human ovarian cancer cells and prostate cancer cells [10,11]. In addition, the proapoptotic effect of protoapigenone was due to, at least in part, its ability to activate JNK and p38 in cancer cells [11]; however, the precise mechanism accounting for this effect remains unclear.…”

Section: Introductionmentioning

confidence: 96%

“…Among them, a novel flavone protoapigenone exhibited significant anti-tumor activities toward HepG2, Hep3B, MCF-7, A549, and MDA-MB-231 with IC 50 values ranging from 0.23 to 3.88 μM. Follow-up studies showed that protoapigenone decreased the viability of cancer cells through induction of cell cycle arrest and apoptosis [10,11]. In a nude mouse xenograft model, protoapigenone also exhibited significant antitumor activity against human ovarian cancer cells and prostate cancer cells [10,11].…”

Section: Introductionmentioning

confidence: 98%

Protoapigenone, a natural derivative of apigenin, induces mitogen-activated protein kinase-dependent apoptosis in human breast cancer cells associated with induction of oxidative stress and inhibition of glutathione S-transferase π

et al. 2010

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Protoapigenone, a natural derivative of the flavonoid apigenin, has been shown to exhibit potent antitumor activity in vitro and in vivo; the precise mechanism of action, however, is not fully elucidated. In this study, we investigated and compared the mechanisms by which protoapigenone and apigenin caused cell death in the human breast cancer MDA-MB-231 cells. Flow cytometry analysis revealed that protoapigenone induced apoptosis with 10-fold greater potency than apigenin. Cancer cells treated with protoapigenone resulted in persistent activation of mitogen-activated protein kinase (MAPK) ERK, JNK, and p38, hyperphosphorylation of Bcl-2 and Bcl-xL, and loss of mitochondrial membrane potential (MMP). The MAPK inhibitors effectively prevented the loss of MMP and apoptosis induced by protoapigenone. Treatment of cells with protoapigenone led to increased levels of reactive oxygen species (ROS) and decreased levels of intracellular glutathione. The thiol-antioxidant N-acetylcysteine abolished protoapigenone-induced MAPK activation, mitochondrial dysfunction, and apoptosis. These results suggest that the induction of oxidative stress preceding the activation of MAPK is required to initiate the mitochondria-mediated apoptosis induced by protoapigenone. Additionally, protoapigenone-induced JNK activation was linked to thiol modification of glutathione S-transferase π (GSTpi), which impeded GSTpi inhibition of JNK. In contrast to protoapigenone, apigenin-induced apoptosis was neither dependent on ROS nor on MAPK. Structure-activity relationship studies suggested that the thiol reacting effect of protoapigenone might be associated with an α, β-unsaturated ketone moiety in the structure of ring B.

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Protoapigenone, a novel flavonoid, inhibits ovarian cancer cell growth in vitro and in vivo

Cited by 52 publications

References 26 publications

Inhibition of ATR-Dependent Signaling by Protoapigenone and Its Derivative Sensitizes Cancer Cells to Interstrand Cross-link–Generating Agents In Vitro and In Vivo

Inhibition of ATR-Dependent Signaling by Protoapigenone and Its Derivative Sensitizes Cancer Cells to Interstrand Cross-link–Generating Agents In Vitro and In Vivo

Lower antioxidative capacity of multidrug-resistant cancer cells confers collateral sensitivity to protoflavone derivatives

Protoapigenone, a natural derivative of apigenin, induces mitogen-activated protein kinase-dependent apoptosis in human breast cancer cells associated with induction of oxidative stress and inhibition of glutathione S-transferase π

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