Resveratrol enhances radiation sensitivity in prostate cancer by inhibiting cell proliferation and promoting cell senescence and apoptosis

Abstract

Radiation therapy (XRT) for treatment of localized prostate cancer (PCA) has outcomes similar to surgery and medical therapy. Toxicities of XRT and the relative radioresistance of PCA limit the effectiveness of this treatment method. Safe and effective radiosensitizing agents are lacking to enhance the effectiveness for XRT for PCA. In this study, the effect of XRT in combination with the radiosensitizing agent resveratrol (RSV) was investigated in a radioresistant PCA cell line, PC-3. Our results show the addition of RSV to XRT (XRT/RSV) synergistically enhanced XRT-induced apoptosis and inhibition of PC-3 proliferation. The antiproliferative effect of XRT/RSV treatment correlated with increased expression of p15, p21, and mutant p53 and decreased expression of cyclin B, cyclin D, and cdk2. Increased apoptosis correlated with increased expression of Fas and TRAILR1. Furthermore, XRT/ RSV had little effect on the expression of p-AKT, whereas it increased the expression level of p-H2A.X, a marker for senescence. These data highlight the potential of RSV as a radiation sensitizer for PCA treatment and warrant further investigation. (Cancer Sci 2012; 103: 1090-1098 P rostate cancer (PCA) is the most common non-cutaneous malignancy and the second leading cause of cancer mortality in elderly men in the USA.(1) Approximately 240 890 new cases of PCA and 33 720 deaths were projected to occur in the USA in 2011.(1) In addition to surgery, chemotherapy, and hormonal therapy, radiation therapy (XRT) is an established therapeutic method for PCA treatment. Radiation therapy is used to treat localized PCA to decrease tumor burden and ameliorate tumor-related symptoms. The efficacy of XRT largely depends on the radiosensitivity of the tumor. Unfortunately, PCA is among the more radioresistant malignant tumors.(2) The high radiation dose associated with XRT for PCA may have severe side-effects, such as impotence, urinary dysfunction, and rectal symptoms; low dose XRT has little effect on PCA. A safe and effective radiosensitising agent is needed to allow a decrease in the radiation dose and side-effects associated with XRT for PCA.Resveratrol (trans-3,4′,5-trihydroxystilbene, RSV) is a polyphenolic compound that occurs naturally in grapes (such as in red wine) and peanuts, as well as in other plant species such as Polygonum cuspidatum and Yucca schidigera.(3-9) The biological function of RSV is very complex. Multiple studies have shown neuroprotective, immunomodulatory, anti-inflammatory, antioxidant, and antitumor functions. In recent years, RSV has been recognized as a promising anticancer agent.(3) Its antitumor functions have been investigated in breast cancer, thyroid cancer, squamous cell carcinoma, HL-60 leukemia, colon cancer, ovarian carcinoma, and PCA cell lines. (10,11) Incubation of the PCA cell line, DU145, with RSV resulted in decreased growth (12) and increased apoptosis of cancer cells.Several studies implicate RSV as a chemotherapy sensitizer, thus, it is reasonable to hypothesize that the combination of RSV w...

Resveratrol induces autophagic apoptosis via the lysosomal cathepsin D pathway in human drug‑resistant K562/ADM leukemia cells

“…Various antitumor effects of Res have been described previously, including the inhibition of DNA polymerase, protein kinase C, cyclooxygenase-2 or interleukin-6 activities, and the suppression of transcription factors such as nuclear factor-κB (4,11,12,21,22). The present study revealed that Res increased autophagosome formation, decreased cell viability and induced apoptotic death in drug-resistant K562/ADM cells.…”

“…Res has been shown to induce cell death through various mechanisms in different cancer cell lines (2,11,12,19). Various antitumor effects of Res have been described previously, including the inhibition of DNA polymerase, protein kinase C, cyclooxygenase-2 or interleukin-6 activities, and the suppression of transcription factors such as nuclear factor-κB (4,11,12,21,22).…”

“…Yan et al (10) reported that Res not only induced leukemia cell apoptosis and erythroid differentiation, but also autophagy. A previous report has indicated that Res induces autophagy in different cancer cell lines via either a pro-survival or pro-death mechanism (11 have demonstrated that Res increases the sensitivity of malignancies, including melanoma, prostate and non-small lung cancer, to chemotherapy (12,13). Although Res is known to induce apoptosis and autophagy in different types of tumor cells, few studies have explored the effects of Res-induced autophagy and its association with apoptosis in drug-resistant leukemia cells.…”

Current insight on anti-tumor effect of natural products

“…In the human malignant B cells, the principle mechanism of resveratrol is to induce the cell apoptosis by activating apoptosis protease-3 and p38 protein kinase pathways. Another mode of resveratrol-induced cell apoptosis follows the paradigm of activating apoptotic protease-2 via a special mechanism in mitochondria (10,16,17). Activated apoptotic protease-2 triggers the conformational change in the Bax/Bak with the release process of mitochondria cytochrome C, apoptosis-inducing factor (AIF) and endonuclease G.…”

Resveratrol enhances the suppressive effects of arsenic trioxide on primitive leukemic progenitors

“…12 Furthermore, resveratrol has been shown to enhance radiation sensitivity in a variety of other malignancies, including melanoma, prostate cancer, and non-small lung cancer. [13][14][15] In the present study, we sought to determine the effects of resveratrol on arsenic trioxide-induced antileukemic responses. We were particularly interested in examining whether resveratrol can potentiate arsenic trioxide-induced autophagy or apoptosis, as our recent studies have established that in addition to apoptotic cell death, induction of autophagy is a key mechanism for the generation of arsenic-induced antileukemic effects on primary leukemic precursors.…”