Milk thistle and prostate cancer: differential effects of pure flavonolignans from Silybum marianum on antiproliferative end points in human prostate carcinoma cells.
Extracts from the seeds of milk thistle, Silybum marianum, are known commonly as silibinin and silymarin and possess anticancer actions on human prostate carcinoma in vitro and in vivo. Seven distinct flavonolignan compounds and a flavonoid have been isolated from commercial silymarin extracts. Most notably, two pairs of diastereomers, silybin A and silybin B and isosilybin A and isosilybin B, are among these compounds. In contrast, silibinin is composed only of a 1:1 mixture of silybin A and silybin B. With these isomers now isolated in quantities sufficient for biological studies, each pure compound was assessed for antiproliferative activities against LNCaP, DU145, and PC3 human prostate carcinoma cell lines. Isosilybin B was the most consistently potent suppressor of cell growth relative to either the other pure constituents or the commercial extracts. Isosilybin A and isosilybin B were also the most effective suppressors of prostate-specific antigen secretion by androgen-dependent LNCaP cells. Silymarin and silibinin were shown for the first time to suppress the activity of the DNA topoisomerase IIalpha gene promoter in DU145 cells and, among the pure compounds, isosilybin B was again the most effective. These findings are significant in that isosilybin B composes no more than 5% of silymarin and is absent from silibinin. Whereas several other more abundant flavonolignans do ultimately influence the same end points at higher exposure concentrations, these findings are suggestive that extracts enriched for isosilybin B, or isosilybin B alone, might possess improved potency in prostate cancer prevention and treatment.
Cancer Res . 2005 May 15;65(10):4448-57
The effect of revised populations on mortality statistics for the United States, 2000.
OBJECTIVES: This report presents revised mortality statistics for the year 2000 based on April 1, 2000, population figures from the 2000 census. Death rates are presented by race, Hispanic origin, sex, age, and cause of death. Life expectancies are presented by race (white and black), sex, and age. The revised statistics are compared with previously published statistics that used July 1, 2000, postcensal population estimates based on the 1990 census. METHODS: Data in this report are based on information from all death certificates filed in the 50 States and the District of Columbia. The statistics presented in this report are computed on the basis of two sets of population figures provided by the U.S. Census Bureau. The first set includes July 1, 2000, postcensal population estimates based on the 1990 decennial census. The second set includes April 1, 2000, populations from the 2000 decennial census bridged to single race categories. RESULTS: Crude death rates were lower for all groups using the April 1, 2000, populations. Age-specific death rates were generally lower for most age groups, except for infants and the very old for which death rates were higher. Age-specific death rates for males were lower for most age groups, except infants and those 75 years and over. For females, with the exception of infants, age-specific death rates were lower. Race-specific pattems by age for the white and black populations were similar to all races combined. For the American Indian population, age-specific death rates were substantially lower for ages under 75 years. For ages 75 years and over, American Indian death rates were dramatically higher. Age-specific death rates for the Asian or Pacific Islander (API) population were higher for ages under 15 years; lower for ages 15-84 years, especially for the 15-34 year age group; and higher for those 85 years and over. For the Hispanic population, age-specific death rates were substantially lower for those age 15-34 years and higher for those age 55 years and over, especially for those age 85 years and over. For the total white and total black populations, the age-adjusted death rate was somewhat higher for males and lower for females. For API the pattern was reversed. For the American Indian and Hispanic populations, age-adjusted death rates were higher for both males and females. For the 15 leading causes of death, age-adjusted death rates based on the April 1, 2000, population figures were lower for heart disease, cancer, chronic liver disease, septicemia, diabetes, chronic lower respiratory diseases, unintentional injuries, homicide, suicide, and hypertension. Age-adjusted death rates were higher for pneumonitis, Alzheimer's disease, and stroke. Rates were unchanged for influenza and pneumonia and nephritis, nephrotic syndrome and nephrosis. Life expectancy at birth was higher for the entire population and both the white and black populations using the April 1, 2000, population figures. It was 0.1 year higher for the whole population as well as for the total white and total black populations. For the total male population, life expectancy at birth was 0.1 year higher while it was 0.2 years higher for the female population. The increase in life expectancy at birth was 0.1 year for both sexes within the white and black populations. This observed gain in life expectancy at birth based on the revised population figures is reversed for life expectancy at the oldest age groups for the whole population and for males. A similar pattern is observed for both white and black males; however, the magnitude of the decline in life expectancy at older ages is much greater among black males. Among females of both race groups and the total population, there is either no change or an increase in life expectancy in the oldest age groups. CONCLUSIONS: Revised death rates and life expectancies are, in many cases, significantly different from previously published mortality statistics calculated using 1990-based postcensal estimates for 2000. Thus, previously published mortality statistics for 2000 using the 1990-based populations will not be comparable to the corresponding statistics that will be published for 2001. The data in this report will provide comparable 2000 data. Efforts are also underway to revise previously published mortality tables for 2000 as well as previously published data for 1991-99.
Natl Vital Stat Rep . 2003 Jun 5;51(9):1-24
Prostate-specific antigen levels in the United States: implications of various definitions for abnormal.
BACKGROUND: The finding that some men with a normal prostate-specific antigen (PSA) level (i.e., less than 4 ng/mL) nonetheless have microscopic evidence of prostate cancer has led to some suggestions that the threshold defining abnormal should be lowered to 2.5 ng/mL. We examined the effect of this lower threshold on the number of American men who would be labeled abnormal by a single PSA test. METHODS: We obtained PSA data on a nationally representative sample of American men 40 years of age and older with no history of prostate cancer and no current inflammation or infection of the prostate gland (n = 1308) from the 2001-2002 National Health and Nutrition Examination Survey. We obtained data on the 10-year risk of prostate cancer death in the pre-PSA era from DevCan, the National Cancer Institute's software to calculate the probability of dying of cancer. RESULTS: Based on NHANES data, approximately 1.5 million American men aged 40 to 69 years have a PSA level over 4.0 ng/mL. Lowering the threshold to 2.5 ng/mL would label an additional 1.8 million men as abnormal, if all men were screened. For men aged 70 years or older, the corresponding numbers are 1.5 and 1.2 million. The proportion of the population affected by different thresholds would vary with age. Among men in their 60s, for example, 17% have a PSA level over 2.5 ng/mL, 5.7% have a PSA level over 4.0 ng/mL, and 1.7% have a PSA level over 10.0 ng/mL. For context, only 0.9% of men in their 60s are expected to die from prostate cancer in the next 10 years. CONCLUSION: Lowering the PSA threshold to 2.5 ng/mL would double the number of men defined as abnormal, to up to 6 million. Until there is evidence that screening is effective, increasing the number of men recommended for prostate biopsy--and the number potentially diagnosed and treated unnecessarily--would be a mistake.
J Natl Cancer Inst . 2005 Aug 3;97(15):1132-7
The unreasonableness of prostate-cancer screening and the ethical problems pertaining to its investigation.
Since the early 1990s, screening with prostate-specific antigen (PSA) testing has increased the incidence of prostate cancer. Any decrease in mortality will not be seen for at least a decade, due to the long natural history of prostate cancer. Death due to prostate cancer is rare, while the prevalence oflocalised tumours is high. The prognosis of these early-detected localised tumours is uncertain, because most patients will die from other causes. Complications of prostate-cancer therapy are common, with high rates of impotence, incontinence and gastrointestinal problems after prostatectomy or radiotherapy. Randomised trials of prostate-cancer screening, notably the 'European randomised screening for prostate cancer' (ERSPC) trial, began with the consent of ethical committees. There is a real uncertainty regarding the benefits of prostate-cancer screening. However, it is clear that these benefits are limited, because prostate-cancer death is rare before the age of 75 years. There is no real uncertainty about the harms of prostate-cancer screening. High prevalence and high rates of treatment complications deduct many disease- and disability-free years from the eligible population (men aged 55-74 years). Therefore, there has been no real uncertainty over the balance of harms and benefits in prostate-cancer screening trials. Days may be added to old age, at the cost of months of disease- and disability-free living. It is not in the best interest of eligible men to participate in these trials. Randomised trials evaluating prostate-cancer screening violate in principle and practice the Helsinki Declaration of the rights of human subjects in medical research.
Ned Tijdschr Geneeskd . 2005 Apr 30;149(18):966-71
Role of Mammalian lignans in the prevention and treatment of prostate cancer.
Prostate cancer is poised to become the most prevalent male cancer in the Western world. In Japan and China, incidence rates are almost 10-fold less those reported in the United States and the European Union. Epidemiological data suggest that environmental factors such as diet can significantly influence the incidence and mortality of prostate cancer. The differences in lifestyle between East and West are one of the major risk factors for developing prostate cancer. Traditional Japanese and Chinese diets are rich in foods containing phytoestrogenic compounds, whereas the Western diet is a poor source of these phytochemicals. The lignan phytoestrogens are the most widely occurring of these compounds. In vitro and in vivo reports in the literature indicate that lignans have the capacity to affect the pathogenesis of prostate cancer. However, their precise mechanism of action in prostate carcinogenesis remains unclear. This article outlines the possible role of lignans in prostate cancer by reviewing the current in vitro and in vivo evidence for their anticancer activities. The intriguing concept that lignans may play a role in the prevention and treatment of prostate cancer over the lifetime of an individual is discussed.
Nutr Cancer . 2005;52(1):1-14
Synergistic anti-cancer effects of silibinin with conventional cytotoxic agents doxorubicin, cisplatin and carboplatin against human breast carcinoma MCF-7 and MDA-MB468 cells.
Significant emphasis is being placed on combination chemotherapy of cancer using cytotoxic agents and naturally occurring chemopreventive agents, having different mechanisms of action with non-overlapping toxicity. In this regard, here we assessed whether a cancer preventive agent silibinin synergizes the therapeutic potential of doxorubicin (Dox), cisplatin or carboplatin, the chemotherapeutic drugs, in both estrogen-dependent and -independent human breast carcinoma, MCF-7 and MDA-MB468 cells, respectively. When tested alone, each of the four agents showed growth inhibition in both the cell lines in a dose- and a time-dependent manner. Based on their growth inhibitory effects, several combinations of silibinin (25-100 microM) with Dox (10-75 nM), cisplatin (0.2-2 microg/ml) or carboplatin (2-20 microg/ml) were next assessed for their synergistic, additive and/or antagonistic efficacy towards cell growth inhibition and apoptotic death. The strongest synergistic effects for cell growth inhibition [combination index (CI) 0.35 for MCF-7 and 0.45 for MDA-MB468 cells] were evident at a silibinin dose of 100 microM plus 25 nM Dox, in both the cell lines. Most of the CIs for other combinations of these three drugs with silibinin also suggested strong synergistic effects for cell growth inhibition in both MCF-7 and MDA-MB468 cells. In quantitative apoptosis studies, combination of silibinin with Dox resulted in much stronger apoptotic death compared to each agent alone in both cell lines. In case of silibinin combination with cisplatin, it showed no additional apoptotic effect in either cell line. Similarly, silibinin plus carboplatin combination showed stronger apoptotic effect only in MCF-7 cells. Together, these results suggest a possible synergism between silibinin and conventional cytotoxic agents for breast cancer treatment, and warrant further in vivo studies in pre-clinical breast cancer models.
Oncol Rep. 2004 Feb;11(2):493-9
Prostate cancer prevention by silibinin.
Several epigenetic alterations leading to constitutively active mitogenic and cell-survival signaling, and loss of apoptotic response are causally involved in self-sufficiency of prostate cancer (PCA) cells toward uncontrolled growth, and increased secretion of pro-angiogenic factors. Therefore, one targeted approach for PCA prevention, growth control and/or treatment could be inhibition of epigenetic molecular events involved in PCA growth, progression and angiogenesis. In this regard, silibinin/silymarin (silibinin is the major active compound in silymarin) has shown promising efficacy. Our extensive studies with silibinin/silymarin and PCA cells have shown the pleiotropic anticancer effects leading to cell growth inhibition in culture and nude mice. The underlying mechanisms of silibinin/silymarin efficacy against PCA involve alteration in cell cycle progression, and inhibition of mitogenic and cell survival signaling, such as epidermal growth factor receptor, insulin-like growth factor receptor type I and nuclear factor kappa B signaling. Silibinin also synergizes the therapeutic effects of doxorubicin in PCA cells, making it a strong candidate for combination chemotherapy. Silibinin/ silymarin also inhibits the secretion of proangiogenic factors from tumor cells, and causes growth inhibition and apoptotic death of endothelial cells accompanied by disruption of capillary tube formation on Matrigel. More importantly, silibinin inhibits the growth of in vivo advanced human prostate tumor xenograft in nude mice. Recently, due to its non-toxic and mechanism-based strong preventive/therapeutic efficacy, silibinin has entered in phase I clinical trial in prostate cancer patients.
Curr Cancer Drug Targets . 2004 Feb;4(1):1-11
A cancer chemopreventive agent silibinin, targets mitogenic and survival signaling in prostate cancer.
There are many epigenetic variables that affect the biological responses of autocrine, paracrine and endocrine regulatory molecules, which determine the growth and development of different cancers including prostate cancer (PCA). One of the focuses of the current cancer chemoprevention studies is the search for non-toxic chemopreventive agents that inhibit mitogenic and cell survival signaling in cancer cells. In general, advanced stage cancer cells harbor many constitutively active mitogenic signaling and anti-apoptotic mechanisms, which make them less dependent on external growth factors as well as resistant to chemotherapeutic agents. In this regard, silibinin (a naturally occurring flavanone) has shown the pleiotropic anticancer effects in different cancer cells. Our extensive studies with PCA have shown that inhibition of mitogenic and cell survival signaling, such as epidermal growth factor receptor, insulin-like growth factor receptor type I and nuclear factor kappa B signaling are the most likely molecular targets of silibinin's efficacy in PCA. We have observed that silibinin inhibits prostate tumor growth in animal models without any apparent signs of toxicity. At the same time, silibinin is also physiologically available in different organs of the body including plasma and prostate, which is generally required for the pharmacological dosing and translational mechanistic studies of the compound. There are substantial amount of data to support the inhibitory effect of silibinin on mitogenic and cell survival signaling in PCA, which are reviewed in the present communication.
Mutat Res. 2004 Nov 2;555(1-2):21-32
Is screening for prostate cancer with prostate specific antigen an appropriate public health measure?
Screening and treatment for prostate cancer is controversial. In the absence of randomized trials, several prominent medical organizations in the United States and Europe have formulated policies that range from enthusiastic support to significant skepticism concerning the efficacy of screening and subsequent treatment for prostate cancer. Sharp rises in the incidence of prostate cancer have occurred whenever PSA testing has been introduced on a wide scale. Unfortunately, it is unclear whether declines in prostate cancer mortality can be attributed to PSA testing. Other explanations include the early use of anti-androgen therapy or changes in environmental factors such as diet. Repeated testing for serum PSA has produced significant shifts in the types of cases being identified and has raised the possibility of significant over-diagnosis of this disease. The European screening trial and the PLCO trial in the US will hopefully provide some insights into the value of population-based testing.
Acta Oncol. 2005;44(3):255-64
Diet, lifestyle and risk of prostate cancer.
Prostate cancer has become a major public health problem worldwide. Yet, the etiology of prostate cancer remains largely unknown. Dietary factors, dietary supplements, and physical activity might be important in the prevention of the disease. In the majority of studies, it was observed that high consumption of meat and dairy products has been linked to a greater risk. In contrast, frequent consumption of fatty fish and tomato products has been associated with a reduced risk. It has been shown consistently that high levels of circulating insulin-like growth factor 1 (IGF-1) are associated with an increased risk of prostate cancer. Dietary factors are also recognized as determinants of circulating IGF-1, thus changes in diet may influence IGF-1 concentrations in serum. Furthermore, increased intake of vitamin E and selenium (from supplements) has been shown in intervention studies to decrease the risk. Possibly, high level of physical activity is also associated with decreased risk of prostate cancer. The accumulated scientific evidence concerning the associations between diet, lifestyle, and risk of prostate cancer development suggests that there are some identified modifiable risk factors that it might be recommended to change in order to decrease the risk for this common cancer site.
Acta Oncol . 2005;44(3):277-81