Differential Effects on Growth, Cell Cycle Arrest, and Induction of Apoptosis by Resveratrol in Human Prostate Cancer Cell Lines

doi:10.1006/excr.1999.4471

Experimental Cell Research

Volume 249, Issue 1, 25 May 1999, Pages 109-115

https://doi.org/10.1006/excr.1999.4471 Get rights and content

Abstract

Epidemiologic studies have suggested that nutrition plays an important role in carcinogenesis and that 30% of cancer morbidity and mortality can potentially be prevented with proper adjustment of diets. Resveratrol, a polyphenol present in red wines and a variety of human foods, has recently been reported to exhibit chemopreventive properties when tested in a mouse skin cancer model system. In this study, we investigated the effects of resveratrol on growth, induction of apoptosis, and modulation of prostate-specific gene expression using cultured prostate cancer cells that mimic the initial (hormone-sensitive) and advanced (hormone-refractory) stages of prostate carcinoma. Androgen-responsive LNCaP and androgen-nonresponsive DU-145, PC-3, and JCA-1 human prostate cancer cells were cultured with different concentrations of resveratrol (2.5 × 10⁻⁵–10⁻⁷M). Cell growth, cell cycle distribution, and apoptosis were determined. Addition of 2.5 × 10⁻⁵M resveratrol led to a substantial decrease in growth of LNCaP and in PC-3 and DU-145 cells, but only had a modest inhibitory effect on proliferation of JCA-1 cells. Flow cytometric analysis showed resveratrol to partially disrupt G₁/S transition in all three androgen-nonresponsive cell lines, but had no effect in the androgen-responsive LNCaP cells. In difference to the androgen-nonresponsive prostate cancer cells however, resveratrol causes a significant percentage of LNCaP cells to undergo apoptosis and significantly lowers both intracellular and secreted prostate-specific antigen (PSA) levels without affecting the expression of the androgen receptor (AR). These results suggest that resveratrol negatively modulates prostate cancer cell growth, by affecting mitogenesis as well as inducing apoptosis, in a prostate cell-type-specific manner. Resveratrol also regulates PSA gene expression by an AR-independent mechanism.

References (36)

J. Muraki et al.
Establishment of new human prostatic cancer cell line (JCA-1)
Urology
(1990)
T.C. Hsieh et al.
Induction of apoptosis and altered nuclear/cytoplasmic distribution of the androgen receptor and prostate-specific antigen by 1α,25-dihydroxyvitamin D₃
Biochem. Biophys. Res. Commun.
(1997)
T.C. Hsieh et al.
Growth modulation of human prostatic cells by interleukin-1 and interleukin-1 receptor antagonists
Cancer Lett.
(1995)
G.J. Soleas et al.
Resveratrol: A molecule whose time has come? And gone
Clin. Biochem.
(1997)
K. Subbaramaiah et al.
Resveratrol inhibits cyclooxygenase-2 transcription and activity in phorbol ester-treated human mammary epithelial cells
J. Biol. Chem.
(1998)
S.L. Parker et al.
Cancer statistics
CA Cancer J. Clin.
(1997)
G.E. Hanks et al.
Cancer: Principles and Practices of Oncology
(1993)
J.T. Isaacs
Prostatic cancer: An age-old problem
S.R. Denmeade et al.
Role of programmed (apoptotic) cell death during the progression and therapy for prostate cancer
Prostate
(1996)
M.E. Kaighn et al.
Establishment and characterization of a human prostatic carcinoma cell line (PC-3)
Invest. Urol.
(1979)

K.R. Stone et al.

Isolation of a human prostate carcinoma cell line (DU-145)

Int. J. Cancer

(1978)

J.S. Horoszewicz et al.

LNCaP model of human prostate carcinoma

Cancer Res.

(1983)

A.B. Miller

Diet and cancer: A review

Rev. Oncol.

(1990)

P. Greenwald et al.

Chemoprevention

CA Cancer J. Clin.

(1995)

W.K. Hong et al.

Recent advances in chemoprevention of cancer

Science

(1997)

M. Jang et al.

Cancer chemopreventive activity of resveratrol, a natural product derived from grapes

Science

(1997)

T.C. Hsieh et al.

Differential expression and regulation of p53 in human prostatic cells

Int. J. Oncol.

(1997)

Cited by (340)

Unexpected Role of pH and Microenvironment on the Antioxidant and Synergistic Activity of Resveratrol in Model Micellar and Liposomal Systems
2022, Journal of Organic Chemistry
Experimental and theoretical studies indicate that resveratrol (RSV, dietary polyphenol that effectively reduces cellular oxidative stress) is a good scavenger of hydroxyl, alkoxyl, and peroxyl radicals in homogeneous systems. However, the role of RSV as a chain-breaking antioxidant is still questioned. Here, we describe pH dependent effectiveness of RSV as an inhibitor of peroxidation of methyl linoleate in Triton X-100 micelles and in 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) liposomes, with the best effectiveness at pH 6 (stoichiometric factors, n, are 4.9 and 5.6, and the rate constants for reaction with peroxyl radicals, k_inh, are 1200 and 3300 M^–1 s^–1 in micellar and liposomal systems, respectively). We propose the mechanism in which RSV-derived radicals are coupled to dimers with recovered ability to trap lipidperoxyl radicals. The formation of such dimers is facilitated due to increased local concentration of RSV at the lipid–water interface. Good synergy of RSV with α-tocopherol analogue in micelles and liposomes is in contrast to the previously reported lack of synergy in non-polar solvents; however, the increased persistency of tocopheroxyl radicals in dispersed lipid/water systems and proximal localization of both antioxidants greatly facilitate the possible recovery of α-TOH by RSV.
Shedding light on the interaction of polydatin and resveratrol with G-quadruplex and duplex DNA: a biophysical, computational and biological approach
2020, International Journal of Biological Macromolecules
Among polyphenols, trans-resveratrol (tRES) and trans-polydatin (tPD) exert multiple biological effects, particularly antioxidant and antiproliferative. In this work, we have investigated the interaction of tPD with three cancer-related DNA sequences able to form G-quadruplex (G4) structures, as well as with a model duplex, and compared its behaviour with tRES. Interestingly, fluorescence analysis evidenced the ability of tPD to bind all the studied DNA systems, similarly to tRES, with tRES displaying a higher ability to discriminate G4 over duplex with respect to tPD. However, neither tRES nor tPD produced significant conformational changes of the analyzed DNA upon binding, as determined by CD-titration analysis. Computational analysis and biological data confirmed the biophysical results: indeed, molecular docking evidenced the stronger interaction of tRES with the promoter of c-myc oncogene, and immunoblotting assays revealed a reduction of c-myc expression, more effective for tRES than tPD. Furthermore, in vitro assays on melanoma cells proved that tPD was able to significantly reduce telomerase activity, and inhibit cell proliferation, with tRES producing higher effects than tPD.
Synthesis, modeling studies and evaluation of E-stilbene hydrazides as potent anticancer agents
2019, Journal of Molecular Structure
A group of new thermodynamically more stable E-2-styrylbenzohydrazide derivatives (5a-i) were synthesized via palladium catalyzed Mizoroki-Heck reaction conditions. All synthesized compounds were characterized by UV-visible, FT-IR, ¹H NMR, ¹³C NMR, mass spectrometry and elemental analysis. Anticancer potential of all synthesized E-stilbene analogues (5a-i) were investigated via cell proliferation assay and apoptosis by Hoechst 33258 staining assay. The most active compound (5e) showed significant anticancer potential against estrogen dependent human breast cancer cells (MCF-7). The cell viability and apoptosis of compound (5e) was found 56 ± 0.06% and 80.09 ± 0.07% respectively as compared to standard drug (Doxorubicin) with cell viability of 62 ± 0.03% and apoptosis 73.69 ± 0.05%. Docking studies revealed higher efficacy of compound (5e) owing to its better binding affinity and ligand efficiency scores (Ki = 0.000076 nMol). All stilbene hydrazides (5a-i) exhibited significant anticancer activity against human breast cancer cells (MCF-7). Therefore, stilbene analogues with hydrazide moiety may offer immense potential for future therapeutic and pharmaceutical applications.
Resveratrol-loaded PLGA nanoparticles mediated programmed cell death in prostate cancer cells
2018, Saudi Pharmaceutical Journal
Resveratrol (RL), a natural polyphenol, is known for its diverse biological effects against various human cancer cell lines. But low aqueous solubility, poor bioavailability, and stability limit its efficacy against prostate cancer. In this study polymeric nanoparticles encapsulating resveratrol (RLPLGA) were designed and their cytotoxic and mode of apoptotic cells death against prostate cancer cell line (LNCaP) was determined. Nanoparticles were prepared by solvent displacement method and characterized for particle size, TEM, entrapment efficiency, DSC and drug release study. RLPLGA exhibited a significant decrease in cell viability with 50% and 90% inhibitory concentration (IC₅₀ and IC₉₀) of 15.6 ± 1.49 and 41.1 ± 2.19 μM respectively against the LNCaP cells. This effect was mediated by apoptosis as confirmed by cell cycle arrest at G1-S transition phase, externalization of phosphatidylserine, DNA nicking, loss of mitochondrial membrane potential and reactive oxygen species generation in LNCaP cells. Furthermore, significantly greater cytotoxicity to LNCaP cells was observed with nanoparticles as compared to that of free RL at all tested concentrations. RLPLGA nanoparticles presented no adverse cytotoxic effects on murine macrophages even at 200 μM. Our findings support the potential use of developed resveratrol loaded nanoparticle for the prostate cancer chemoprevention/ chemotherapy with no adverse effect on normal cells.
Oxidative Stress: The Role of Antioxidant Phytochemicals in the Prevention and Treatment of Diseases
2024, International Journal of Molecular Sciences
Targeting Peroxisome Proliferator-Activated Receptor-β/δ, Reactive Oxygen Species and Redox Signaling with Phytocompounds for Cancer Therapy
2024, Antioxidants and Redox Signaling

View all citing articles on Scopus

^☆: This study was supported in part by the Vivian Wu-Au Memorial Cancer Research Fund and an unrestricted grant from the Philip Morris Company. We thank Dr. Zhou Bao-sen for statistical advice. We give special thanks to Drs. Frank Traganos and Darzynkiewicz of Brander Cancer Research Institute, New York Medical College, for providing assistance with flow cytometric analysis.

^☆☆: V. T. DeVita, Jr.S. HellmanS. A. Rosenberg

²: To whom correspondence and reprint requests should be addressed at Room 133, Department of Biochemistry and Molecular Biology, Basic Sciences Bldg., New York Medical College, Valhalla, NY 10595. Fax: (914) 594-4058. E-mail:[email protected].

View full text

Regular ArticleDifferential Effects on Growth, Cell Cycle Arrest, and Induction of Apoptosis by Resveratrol in Human Prostate Cancer Cell Lines☆,☆☆

Abstract

Urology

Biochem. Biophys. Res. Commun.

Cancer Lett.

Clin. Biochem.

J. Biol. Chem.

Cancer statistics

CA Cancer J. Clin.

Cancer: Principles and Practices of Oncology

Prostatic cancer: An age-old problem

Role of programmed (apoptotic) cell death during the progression and therapy for prostate cancer

Prostate

Establishment and characterization of a human prostatic carcinoma cell line (PC-3)

Invest. Urol.

Isolation of a human prostate carcinoma cell line (DU-145)

Int. J. Cancer

LNCaP model of human prostate carcinoma

Cancer Res.

Diet and cancer: A review

Rev. Oncol.

Chemoprevention

CA Cancer J. Clin.

Recent advances in chemoprevention of cancer

Science

Cancer chemopreventive activity of resveratrol, a natural product derived from grapes

Science

Differential expression and regulation of p53 in human prostatic cells

Int. J. Oncol.

Regular Article
Differential Effects on Growth, Cell Cycle Arrest, and Induction of Apoptosis by Resveratrol in Human Prostate Cancer Cell Lines☆,☆☆