A novel synthetic protoapigenone analogue, WYC02-9, induces DNA damage and apoptosis in DU145 prostate cancer cells through generation of reactive oxygen species

Chen, Huei Mei; Chang, Fang Rong; Hsieh, Ya Ching; Hsieh, Kun Chou; Tsai, Lih Min; Lin, An Shen; Wu, Yang Chang; Yuan, Shyng‐Shiou F.

doi:10.1016/j.freeradbiomed.2011.01.015

Cited by 37 publications

(33 citation statements)

References 42 publications

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“…The same concentration of compounds did not affect the cell cycle in corresponding non-MDR cells. The effects of compounds 5 and 6 in MDR cells are in accordance with those observed previously in prostate, lung and colorectal carcinoma cell lines with protoapigenone (1) and its derivative WYC02-9 (2), which were shown to cause cell cycle perturbation and induce G2/M arrest [26][27][28]. Additionally, compound 6 significantly increased ROS/RNS production in glioma MDR cells and this was accompanied by a decrease in mRNA MnSOD and HIF-1α expression.…”

Section: Discussionsupporting

confidence: 87%

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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Section: Discussionsupporting

confidence: 87%

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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“…Previously, WYC02 and WYC0209 were shown to cause DNA strand breaks and apoptosis in lung and prostate cancers (18,20), suggesting that inducing DNA damage may be the potential mechanism underlying the anticancer effect of WYCs. To test this hypothesis, we investigated the cytogenetic effect of WYC02 on CHO cells (Fig.…”

Section: Wyc02 Induces Chromosomal Aberrations But Does Not Produce Mmentioning

confidence: 99%

“…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%

“…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. To date, the biomolecular actions and implications of this WYC-mediated interference are mostly undetermined.…”

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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“…In an attempt to increase anticancer activity, the synthesis of new flavonoid analogues has been conducted (7). Moreover, the anticancer activity of these synthetic compounds has been observed in various cancer cell lines in vitro (8)(9)(10)(11)(12)(13). We previously reported the production of synthetic flavonoids (14-16) that exert various biological activities in vitro (17).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the anticancer activities of thioflavanone and thioflavone in human breast cancer cell lines

Kim

2011

Int J Mol Med

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Abstract. This study investigated the anticancer effects of thioflavanone and thioflavone in the MCF-7, MDA-MB-231 and MDA-MB-453 human breast cancer cell lines. Cells were treated with either thioflavanone or thioflavone from 1 to 100 µM for 24 h, and their anti-proliferative activity and cytotoxicity was determined. Thioflavanone and thioflavone possessed similar anti-proliferative activities; their IC 50 values were 62-89 and 74-128 µM, respectively, although the cytotoxicity of thioflavanone was significantly higher and occurred in a dose-dependent manner. Taken together, these results suggest that thioflavanone significantly inhibits cellular proliferation with weak cytotoxicity to a greater extent than thioflavone, and induces apoptosis in human breast cancer cell lines. Moreover, thioflavanone, but not thioflavone, induces apoptosis via p53-dependent expression of Bax. IntroductionFlavonoids are a group of over 6,000 phytochemicals that include flavones, flavonols, flavanones, and isoflavones in palnts, and are usually present almost exclusively in the form of β-glycosides. According to several epidemiological studies, flavonoids may reduce the risk of developing cancer and cardiovascular disease (1-3). Due to their benefit to human health, the biological activity of flavonoids has been extensively examined in terms of their antitumor, anti-inflammatory, and antioxidant capacity in vitro (4,5).The common structural feature of flavonoids is the flavan nucleus, which consists of 15 carbon atoms arranged in 3 rings (phenylchromanone structure, C6-C3-C6). Rings A and B are benzene rings and ring C is a heterocyclic pyran or pyrone. A number of the anticancer mechanisms of flavonoids have been shown to be associated with their structure-activity relationships (SAR) (6). Recently, much research has aimed to understand the relationship between structural modifications and biological activity. In an attempt to increase anticancer activity, the synthesis of new flavonoid analogues has been conducted (7). Moreover, the anticancer activity of these synthetic compounds has been observed in various cancer cell lines in vitro (8-13). We previously reported the production of synthetic flavonoids (14-16) that exert various biological activities in vitro (17). Sulfur-containing flavonoid analogues have activities greater than the molecules from which they were derived. For example, synthetic thioflavopiridols may act as selective CDK1 inhibitors in human tumor cell lines (18). Our previous report (17) suggested that synthetic flavanone derivatives were more potent than flavanone in an antiproliferation assay using human breast cancer cells.In the present study, we investigated the anticancer activities of thioflavanone and thioflavone in vitro. We postulated that thioflavanone and thioflavone, which are synthesized as the thio analogues, may possess greater biological activities than their precursors. Materials and methodsSynthesis of thioflavanone and thioflavone. Treatment of thiosalicylic acid (denoted as 1 in Fig. 1) ...

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A novel synthetic protoapigenone analogue, WYC02-9, induces DNA damage and apoptosis in DU145 prostate cancer cells through generation of reactive oxygen species

Cited by 37 publications

References 42 publications

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

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

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

Evaluation of the anticancer activities of thioflavanone and thioflavone in human breast cancer cell lines

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