Persimmon Leaf Flavonols Enhance the Anti-Cancer Effect of Heavy Ion Radiotherapy on Murine Xenograft Tumors

Abstract

The cell cycle checkpoint system play a pivotal role in the cellular DNA damage response, and the discovery of checkpoint inhibitors is expected to sensitize current cancer therapies. Checkpoint signaling cascades are critically modulated by ATM (ataxia telangiectasia-mutated) and its related molecules. Generally, ATM primarily responds to ionizing irradiation-induced DNA double-strand breaks. Heavy ions from an accelerated carbon ion beam have been used to cure cancer because they are more effective than ionizing irradiation such as X-ray and γ-radiation in terms of biological damage. In a previous study, we demonstrated that a persimmon leaf flavonol (PLF) promoted the cytotoxic effect of chemotherapeutic agents on cancer cells through inhibition of checkpoint activities, especially in the ATM dependent pathway. The present study investigated whether PLF inhibits checkpoint activity during the DNA damage response induced by heavy ion irradiation. Treatment with PLF significantly increased the cytotoxicity of heavy ion irradiation in A549 adenocarcinoma cells. The phosphorylation of checkpoint proteins such as p53, SMC1, and Chk1 was increased by heavy ions. PLF reduced the phosphorylation of checkpoint proteins. Pre-treatment with PLF significantly prevented the decrease of mitotic cells in heavy ion-exposed cells. We further evaluated tumor volume in SCID mice inoculated with human lung adenocarcinoma A549 cells. The combination treatment of PLF and heavy ion resulted in a decrease of tumor volume compared with controls, although PLF itself did not exhibit any effect. These results indicate that PLF inhibits tumor growth through modulation of the DNA damage response. PLF may be useful for clinical application in combination with heavy ion radiotherapy.

Antitumor Potential of Immunomodulatory Natural Products

“…Persimmon (Diospyros kaki L.) leaves, an Asian traditional medicine agent, containing mainly flavonoids, have been also described for their beneficial pharmacological effects including antitumor [80], hypoglycemic [81], antioxidant [82], and anti-inflammatory [82]. Li Chen et al [83] identified four main flavone and flavonol glycosides, rutin (18), quercetin (16), kaempferol (14), and myricetin ( 19), described to have anticancer effect to leukemia, colorectal cancer, neuroblastoma, melanotic melanoma [84], and human prostate cancer cell line [85].…”

Antitumor and immunomodulatory activities of total flavonoids extract from persimmon leaves in H22 liver tumor-bearing mice

“…The main constituents found in persimmon leaves include flavonoids, terpenoids, naphthoquinones, coumarins, tannins, sterols, organic acids, fatty acids, and volatile oil 8 . The reported beneficial pharmacological effects of persimmon leaves include antitumor 9 , hypoglycemic 10 , antioxidant 11 , anti-inflammatory 12 , anti-bacterial 13 , antihypertensive 14 , anti-hyperlipidemia 15 , and cardiovascular protective 16 activities. Our previous studies indicated that the ethyl acetate extract of persimmon leaves (2 g/kg) possessed antitumor activity against H 22 hepatoma and S 180 Sarcoma with a tumor inhibition rate of 50.5% and 38.2%, respectively 17 .…”

“…As flavonoids are the main bioactive constituents in the ethyl acetate extract of persimmon leaves, we hypothesize that the total flavonoids extract from the persimmon leaves may contribute to the antitumor and immunomodulatory activities of the ethyl acetate extract from the persimmon leaves. Recent studies reported in vitro proliferative and in vivo antitumor activities of flavonoids extracted from persimmon leaves against lung and prostate cancers 9 , 18 . As to our knowledge, there is no report on the cancer immunomodulation effect of total flavonoids extract of persimmon leaves (PLF) and there is no report of its efficacy against liver cancer.…”

Unveiling major ethnopharmacological aspects of genus Diospyros in context to its chemical diversity: A comprehensive overview

“…In addition, it significantly increased the cytotoxicity triggered by heavy ion irradiation in A549 adenocarcinoma cells. Pretreatment with persimmon leaf flavonol significantly restrained the decrease of mitotic cells in heavy ion‐exposed cells and reduced tumor mass volume, although it solely did not reveal any effect (Kawakami et al, 2013). On the contrary, in a more recent study, it has been reported that persimmon leaf flavonol exhibited antiproliferative action and induce apoptosis in PC‐3 cells by the activation of oxidative stress and mitochondrial‐related apoptosis (Ding et al, 2017).…”