Cytotoxic Effects of Ellagitannins Isolated from Walnuts in Human Cancer Cells

Abstract

Walnuts contain many bioactive components that may slow cancer growth. A previous report showed that a diet supplemented with walnuts decreased the tumor size formed by MDA-MB-231 human cancer cells injected into nude mice. However, the mechanism of action was never determined. We characterized the effects of a methanol extract prepared from walnuts on human MDA-MB-231, MCF7, and HeLa cells. The extract was cytotoxic to all cancer cells. We identified compounds from the methanol extract that induced this cytotoxicity. The predominant compounds were Tellimagrandin I and Tellimagrandin II, members of the ellagitannin family. We also show a walnut extract decreases the intracellular pH, depolarizes the mitochondrial membrane with release of cytochrome c and phosphatidylserine flipping. The antimitogenic effects of walnut extract were associated with a twofold reduction of mitochondria respiration. These results suggest impairment of mitochondrial function and apoptosis as relevant mechanism of anticancer effects of the walnut extract.

Recent Advances in Anticancer Activities and Drug Delivery Systems of Tannins

“…ETs are bioactive polyphenols that are abundant in some fruit herbs such as fructus chebulae, Phyllanthus emblica , and Punica granatum L . In contrast to the rather limited distribution of GTs in nature, ETs are typical constituents of many plant families, with more than 500 natural products characterized so far, such as davidiin, tellimagrandin I/II, vescalagin, and so on. ETs have previously been shown to exhibit in vitro and in vivo anticancer properties such as cell‐cycle arrest and apoptosis induction against various cancer cell lines, including liver, estrogen‐responsive breast, leukemia, and colon cancer cells, as well as inhibition of tumor formation and growth in animals.…”

“…The results suggested that both antiproliferative and multigene regulatory action could be induced by ET‐modified miRNA expression in HepG2 cancer cells. Additionally, tellimagrandin I/II, belonging to ET family as the major compounds from methanol extract of walnuts, showed anticancer effects via impairment of mitochondrial function by decreasing intracellular pH and depolarizing mitochondrial membrane with release of cytochrome c as well as phosphatidylserine flipping . Interestingly, davidiin, which was isolated from P. capitatum extract, was investigated as a potential anticancer ET with the ability of inhibiting cancer cell growth via downregulating the enhancer of zeste homolog 2 (EZH2) and inducing apoptosis as well as suppressing tumor growth in xenograft models of Bel7404 .…”

Dose‐Dependent Increases in Ellagitannin Metabolites as Biomarkers of Intake in Humans Consuming Standardized Black Raspberry Food Products Designed for Clinical Trials

“…The BRB, for example, when evaluated by a non‐targeted metabolomic analysis showed over 4000 different UPLC peaks. [ 50 ] We chose to study BRBs based upon the anti‐cancer bioactivity of relevant phytochemicals in vitro [ 12–14,17,41,54,55 ] and accumulating studies of cancer preventive activity in rodent models. [ 16,19,40,47,56,57 ] Notably, due to the modest exposure of most populations to BRBs and the lack of specificity of berry intake on food frequency questionnaires, it is unlikely that epidemiological studies will provide insightful data regarding BRBs and cancer risk or other health outcomes.…”

Gallic Acid and Gallates in Human Health and Disease: Do Mitochondria Hold the Key to Success?

“…The pentagalloylglucose (1,2,3,4,6‐penta‐O‐galloyl‐beta‐ d ‐glucose), a pentagallic acid–glucose ester inhibits complex I, II, and III, but not complex IV, in a dose‐dependent manner and damages the mitochondrial membrane, causing reduction of ATP synthesis . Ellagitannins are another group of polygalloyl derivatives, which inhibit mitochondrial respiration associated with membrane damage, cytochrome c release, and subsequent apoptosis induction . PG has a different effect on mitochondrial respiration as it stimulates the respiratory oxygen uptake via oxidation of n ‐propanol obtained from PG degradation, whereas the gallic acid produced in the same reaction does not affect the oxygen consumption .…”