Apoptosis‐inducing activity of hydroxylated polymethoxyflavones and polymethoxyflavones from orange peel in human breast cancer cells

Abstract

Sweet orange (Citrus sinensis L.) peel is a rich resource of flavonoids, especially polymethoxyflavones (PMFs). Citrus flavonoids exert a broad spectrum of biological activity, including antiproliferative and proapoptotic effects in cancer cells. We have recently shown that individual PMFs from orange peel induce Ca(2+)-mediated apoptosis in human breast cancer cells and that hydroxylation of PMFs is critical for enhancing their proapoptotic activity. Here, we report that the fraction of orange peel extract containing a mixture of non-hydroxylated PMFs (75.1%) and hydroxylated PMFs (5.44%) and the fraction containing only hydroxylated PMFs (97.2%) induce apoptosis in those cells as well. Treatment of MCF-7 breast cancer cells with these fractions inhibited growth and induced apoptosis associated with an increase in the basal level of intracellular Ca(2+). Effective concentrations of the hydroxylated PMFs fraction in inhibiting growth, inducing apoptosis, and increasing intracellular Ca(2+) were lower than those of the non-hydroxylated PMFs fraction. Our results strongly imply that bioactive PMFs from orange peel exert proapoptotic activity in human breast cancer cells, which depends on their ability to induce an increase in intracellular Ca(2+ )and thus, activate Ca(2+)-dependent apoptotic proteases.

Monodemethylated polymethoxyflavones from sweet orange (Citrus sinensis) peel Inhibit growth of human lung cancer cells by apoptosis

“…Our results demonstrated that hydroxylated PMFs, i. e., 5HPMF and 5HHMF, have much stronger inhib- itory effect on H1299 cell growth than their permethoxylated counterparts, i. e., nobiletin and HMF, respectively. Our results are in agreement with previous reports that showed potent anticancer effects of 5-hydroxylated PMFs in leukemia and breast cancer cell lines [6,7,11,12]. The only chemical structural difference between 5HPMF and nobiletin, or between 5HHMF and HMF, is the substitution of the methoxy group with hydroxyl in 5-position.…”

Chemoprevention of colonic tumorigenesis by dietary hydroxylated polymethoxyflavones in azoxymethane‐treated mice

“…This anti-proliferative and pro-apoptotic activity could be an important mechanism for hydroxylated PMFs to inhibit AOM-induced colon tumor formation. Previous in vitro studies demonstrated that hydroxylated PMFs and PMFs induce apoptosis in mature adipocytes and various cancer cells via activation of Ca 21 -dependent calpain and Ca 21 /calpain-dependent caspase-12 [52][53][54], implying the pro-apoptotic effects of dietary hydroxylated PMFs in AOM-treated colonic tumorigenesis through Ca 21 -medicated pathway. In summary, our study showed in vivo chemopreventive efficacy including anti-inflammatory, anti-proliferative, antiangiogenic and apoptosis-inducing effects of dietary hydroxylated PMFs in AOM-induced colonic tumorigenesis.…”

Inhibitory effects of 5‐hydroxy polymethoxyflavones on colon cancer cells

“…Previously, we have reported that 5HPMF and 5HHMF were more potent in inhibiting the growth of human lung cancer cells than nobiletin and HMF [6]. Others also demonstrated that 5-hydroxy PMFs were potent agents in inhibiting leukemia and breast cancer cell growth [4,7,8,13]. Moreover, hydroxylation of other methoxy groups in the PMFs can also enhance their bioactivities, e.g.…”