Caffeic acid phenethyl ester induces radiosensitization via inhibition of DNA damage repair in androgen‐independent prostate cancer cells

Abstract

In the present study, we evaluated the radiomodulatory potential of caffeic acid phenethyl ester (CAPE), an active component of traditional herbal medicine propolis. CAPE has been identified as a potent anticancer agent in multiple cancer types and is reported to have the dual role of radioprotection and radiosensitization. However, the radiomodulatory potential of CAPE in prostate cancer (PCa), which eventually becomes radioresistant is not known. Therefore, we studied the effect of cotreatment of CAPE and gamma radiation on androgen-independent DU145 and PC3 cells. The combination treatment sensitized PCa cells to radiation in a dosedependent manner. The radiosensitizing effect of CAPE was observed in both cell lines. CAPE enhanced the level of ionizing radiation (IR)-induced gamma H2AX foci and cell death by apoptosis. The combination treatment also decreased the migration potential of PCa cells. This was confirmed by increased expression of E-cadherin and decrease in vimentin expression. CAPE sensitized PCa cells to radiation in vitro and induced apoptosis, augmented phosphorylation of Akt/mTOR, and hampered cell migration. At the mechanistic level, co-treatment of CAPE and IR inhibited cell growth by decreasing RAD50 and RAD51 proteins involved in DNA repair. This resulted in enhanced DNA damage and cell death. CAPE might represent a promising new adjuvant for the treatment of hormone-refractory radioresistant PCa.

Molecular and Cellular Mechanisms of Propolis and Its Polyphenolic Compounds against Cancer

“…Therapeutic effects of propolis on numerous diseases, such as infections, hypertension, cardiovascular disorders, diabetes, allergies, asthma, and cancer, are assigned to its anti-oxidative, immuno-modulatory, and anti-inflammatory properties [ 3 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 88 ]. These diseases are accompanied by mitochondrial dysfunction and increased ROS production and the enzymatic and non-enzymatic oxidation of polyunsaturated fatty acids (PUFAs).…”

“…Many lines of evidence suggest that immunomodulation by propolis and its polyphenolic/flavonoid components is an important contributing factor to the antitumor and antimetastatic activities of these compounds. Flavonoids may induce the immune system [ 3 , 16 , 17 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 92 , 214 , 215 , 216 , 217 , 218 , 220 , 221 , 222 , 223 ], and act as powerful free radical scavengers [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 39 , 40 , 41 , 42 , 58 , 63 ]. Accordingly, a high dietary intake of flavonoids from propolis is associated with a reduced risk of cancer at different anatomical sites [ 3 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ].…”

“…Their biological effects are mostly attributed to phenolic compounds. Results of previous research suggest that honeybee products and their flavonoid components are particularly promising as antitumor [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ], immunomodulatory [ 21 , 22 , 23 , 24 , 25 , 26 , 27 ], and radioprotective [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ] agents. Results of epidemiological studies also support the important contribution of foodstuffs of vegetable origin in the prevention of numerous illnesses, including cancer [ 36 , 37 , 38 , 39 , 40 ].…”

Advances in Dietary Phenolic Compounds to Improve Chemosensitivity of Anticancer Drugs

“…Caffeic acid is moderately available in sunflower seeds, applesauce, apricots, and prunes. Caffeic acid phenethyl ester (CAPE), a central component of propolis, has also been investigated for its chemo-sensitizing [ 51 , 52 ] and radio-sensitizing [ 53 ] effects against various types of cancer. The radio-sensitizing effect of this substance was evaluated in 2005 by Chen, et al [ 49 ] against CT26 colorectal adenocarcinoma cells and in vivo on BALB/c mice implanted with these cells.…”

“…These authors noted, in vitro, an improvement in the destruction of CT26 cells by ionizing radiation (IR) and, in vivo, an extension of animal survival and a marked inhibition of tumor growth compared to radiotherapy alone. The mechanism of action explaining this radio-sensitivity was elucidated very recently on prostate cancer cells (DU145 and PC3) by co-treatment using gamma radiation (GR) and CAPE [ 53 ]. Results showed that this combined treatment sensitizes the cells to radiotherapy by reducing the RAD50 and RAD51 proteins and the cell migration potential, mainly by inhibiting DNA damage repair.…”