Abstract 1232: Antiproliferative, antioxidant and antiapoptotic effect of rhamnetin in human prostate cancer cells

Abstract

Persistent oxidative stress due to generation of reactive oxygen species (ROS) has been associated with malignancy and cancer progression. Using a panel of human prostate cancer cells, we observed increased production of intracellular ROS, compared to normal human prostate epithelial cells, accompanied by elevated expression of antioxidant enzymes viz. superoxide dismutase, catalase, peroxiredoxin-1 and thioredoxin that may be a likely mechanism to endure increased oxidative stress. There is a need for novel antioxidant agent that can effectively suppress the generation of increased ROS in cancer cells. Rhamnetin (3,5,3,4-tetrahydroxy-7-methoxyflavone), remains highest on oxygen radical absorbance capacity scale, however its anti-proliferative activities has not been assessed. Rhamnetin is an O-methylated flavonol, abundantly present in cloves, sweet annie, annual wormwood, green vegetables and orchard grass. Previous studies (Shukla et al. Proc. Amer. Assoc. Cancer Res. 102: 5576, 2011) using androgen-responsive human prostate cancer LNCaP and androgen-refractory PC-3 cells, we have demonstrated that rhamnetin possess anticancer activity, induces apoptosis, and inhibits cancer cell growth. In the present study we assessed the antioxidant and anti-proliferative ability of rhmanetin in prostate cancer. Treatment of LNCaP and PC-3 cells with 100μM paraquat, an oxidative stress-inducing agent, induced cellular proliferation in both these cells. Treatment of cells with 5-80μM rhamnetin significantly decreased paraquat-induced ROS production and inhibited cell proliferation in dose-dependent manner. Similar effects were noted with the addition of recombinant Klotho protein to these cells, which is known to offer resistance to oxidative stress at the cellular level. Rhamnetin treatment also increased Klotho protein levels in both cell lines, along with increase in the expression of p53 and p21/waf1. Furthermore, rhamnetin treatment resulted in the increased expression of caspase-3, caspase-9 causing induction of apoptosis, which may be one of the protective mechanism(s) to decrease cell proliferation and enhance resistance to oxidative stress in cancer cells. Taken together, these results demonstrate that rhamnetin acts as a potent antioxidant agent, reduces intracellular ROS levels, increases Klotho protein expression, induces apoptosis in prostate cancer cells, which may have a significant role in the inhibition of prostate cancer progression. Citation Format: Christine Oak, Natarajan Bhaskaran, Sanjay Gupta, Sanjeev Shukla. Antiproliferative, antioxidant and antiapoptotic effect of rhamnetin in human prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1232. doi:10.1158/1538-7445.AM2014-1232

Rhamnetin Exhibits Anti‐Tuberculosis Activity and Protects against Lung Inflammation

“…Rhamnetin (3,5,3′,4′‐tetrahydroxy‐7methoxyflavone), shown in Figure (a), can be found in cloves; coriander; and fruits such as apple, pomace, and sour cherries . Recently, we reported the anti‐inflammatory properties of rhamnetin, which was able to suppress mouse tumor necrosis factor‐α, mouse macrophage inflammatory protein (mMIP)‐1, and mMIP‐2 cytokine production in lipopolysaccharide (LPS)‐stimulated macrophages .…”

Role of bio‐flavonols and their derivatives in improving mitochondrial dysfunctions associated with pancreatic tumorigenesis

“…193 Rhamnetin therapy also boosted Klotho protein levels, which imparts resistance to oxidative stress in prostate tumor cells by increasing p53 and p21 expression. 194 Rhamnetin can make hepatocellular carcinoma cells more responsive to molecular targeting drugs like sorafenib or radiation therapy using 60Co-γ. 195 The notch-1 pathway is the potential target of rhamnetin for combating the multidrug resistance (MDR) process and improving the stress response, cell survival, and EMT in hepatic tumor cells.…”

“…Rhamnetin acts on the p38/MAPK, ERK, JNK, and COX‐2 pathways in IFN‐γ or LPS‐induced cells to show antiinflammatory effects 193 . Rhamnetin therapy also boosted Klotho protein levels, which imparts resistance to oxidative stress in prostate tumor cells by increasing p53 and p21 expression 194 . Rhamnetin can make hepatocellular carcinoma cells more responsive to molecular targeting drugs like sorafenib or radiation therapy using 60Co‐γ 195 .…”