Kanser prostat merupakan ancaman terbesar kematian akibat kanser di kalangan lelaki. Terdapat keperluan utama bagi terapi kurang toksik tetapi berkesan untuk merawat kanser prostat.
Dengan memulakan amalan mengambil Jus Delima atau sediaan ekstrak delima dapat menghindarkan anda daripada risiko kanser prostat dan juga kanser jenis lain.
Penyelidikan terkini menunjukkan bahawa jus delima (PJ) dan / atau ekstrak buah delima (PE) dengan ketara menghalang pertumbuhan sel-sel kanser prostat. Dalam model murine pra-klinikaljus delima (PJ) dan / atau ekstrak buah delima (PE) menghalang pertumbuhan angiogenesis tumor prostat.
Baru-baru ini, kita telah menunjukkan bahawa tiga komponen PJ, luteolin, asid ellagic dan asid punicic bersama-sama, mempunyai kesan mencegah pertumbuhan kanser prostat, angiogenesis dan metastasis.
Prostate cancer (PCa) is the second-leading cause of cancer-related deaths in men in the United States. The American Cancer Society has estimated that a total of 233,000 new cases will be diagnosed and 29,480 men will die of PCa in 2014 [
1]. Various treatments are available, some more effective than others. To date there is no real cure for the disease beyond surgery and/or radiation when used at early stages of the disease. When recurrence occurs, the cancer can be controlled with hormone ablation therapy (Leuprolide/Lupron
®), taking advantage of the growth dependence of PCa on testosterone. However, over time, the cancer develops ways to bypass hormone dependence, becoming highly aggressive, castration-resistant prostate cancer (CRPC) that metastasizes to the lung, liver and bone [
2,
3]. In addition to the hormone ablation, chemotherapy is available today to treat CRPC, but it is not very effective because PCa cells divide slowly and, like with prostatectomy, the treatments are aggressive and have many side effects [
4]. As a result, researchers are looking for novel strategies to treat PCa. FDA approved sipuleucel-T (Provenge
®) is an autologous cellular immunotherapy to treat metastatic PCa. In the clinical trial on which this approval was granted, the median overall survival rate of patients who received sipuleucel-T improved by only 4.5 months. Treatment is costly but some patients survived much longer than the median [
5]. Novel androgen receptor (AR) antagonists such as enzalutamide (Xtandi
®) and androgen biosynthesis inhibitors such as abiraterone (Zytiga
®), have shown great promise as androgen deprivation therapies to prolong overall survival rate among patients with metastatic PCa [
6,
7]. Another novel drug, Cabozantinib, is a potent dual inhibitor of the tyrosine kinases c-MET and vascular endothelial growth factor receptor 2 (VEGFR2), and has been shown to reduce or stabilize metastatic bone lesions in CRPC patients [
8,
9]. These treatments against PCa are summarized in . However, all of these treatments have adverse side effects.
Summary of current treatments against prostate cancer. The current treatments include surgery, radiation, chemotherapy, androgen-deprivation therapy (ADT), immunotherapy, and targeted therapy.
More recently, there has been a renewed push to identify natural remedies to fight prostate cancer. Among the latter is pomegranate juice (PJ) and/or pomegranate extracts (PE). The pomegranate fruit is derived from the tree
Punica granatum, is edible and is cultivated in Mediterranean countries, Afghanistan, India, China, Japan, Russia, and some parts of the United States [
10,
11]. Pomegranates have been used in folk medicine for centuries. They possess strong antioxidant, anti-inflammatory, anti-atherogenic effects, and some studies have suggested that they also may have anti-tumorigenic properties [
12,
13,
14,
15]. In fact, the antioxidant activity of pomegranates has been shown to be higher than that of red wine or green tea, two dietary substances that are showing promise in preclinical prostate cancer models and in patients with PCa [
16]. In this review we discuss data on the effects of PJ and PE on PCa cells in cell culture, in animal models and in clinical trials as well as specific components of the pomegranate fruit and how they have been used to study the mechanisms involved in prostate cancer progression.
The pomegranate fruit can be divided into three major anatomical components: the juice, the pericarp and the seeds. These discrete components of the pomegranate fruit have been found to exert anti-proliferative and anti-invasive effects on PCa cells [
30]. The juice and pericarp contain a rich complement of two types of polyphenolic components which have attracted interest for recent research: anthocyanins which give the juice its red color [
74], such as delphinidin, cyanidin and pelargonidin, and hydrolyzable tannins, such as the punicalagin and gallagic acid [
13,
75,
76]. Other polyphenolic components of possible interest include kaempferol, quercetin and luteolin [
75,
77,
78]. The seed oil, which is comprised of 65%–80% conjugated fatty acids, also contains many compounds of interest with known antioxidant and anti-cancer activities [
79]. The predominant component among these fatty acids is punicic acid (present at about 1–5 µg/mL in juice) [
80,
81].
PJ is a very complex mixture of components and is found in many different formulations, it is important to identify specific components that can replace the effects of the juice on growth and metastasis. Ellagitannin, the most abundant polyphenol present in PJ, is hydrolyzed to ellagic acid (present at about 50–200 µg/mL in juice) that is then converted to urolithin A by gut microflora [
82,
83]. Oral administration of ellagitannin-enriched PE not only inhibited LAPC4 xenograft tumor growth in SCID mice [
84] but also inhibited tumor-associated angiogenesis [
85]. In addition, ellagitannin inhibited the expression of androgen receptor (AR) and androgen synthesizing enzymes, such as 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) and steroid 5α reductase type I (SRD5A1), in PCa cells [
24]. Ellagic acid was shown to possess anti-tumorigenic activities on lung, cervical, colon, breast and prostate cancer cells [
86,
87,
88]. Recently it was shown that ellagic acid and its metabolite urolithin A synergistically inhibited cell growth and induced apoptosis in DU145 and PC3 cells [
89]. These investigators also found that ellagic acid is more effective than urolithin A.
Several studies have shown anti-proliferative effects of luteolin (present at about 1 µg/mL in juice) on human squamous liver and colon cancer cells [
90,
91,
92]. Using a Matrigel invasion assay, it was shown that luteolin inhibits invasion of PC3 cells via increasing the expression of
E-cadherin [
93]. It is established that decreased expression of
E-cadherin, one important cell-cell adhesion molecule [
94,
95], results in a loss of cell-cell adhesion and increased cell invasion [
96]. It was found that luteolin increased the expression of
E-cadherin, and that knockdown of
E-cadherin reversed the effect of luteolin on invasion of PC3 cells; in addition, intraperitoneal administration of luteolin three times a week reduced lung metastasis of PC3 xenograft tumors in nude mice [
93]. In addition, luteolin has been shown to inhibit PCa tumor growth via targeting angiogenesis. After primary xenograft PC3 tumors have developed in nude mice, it was found that intraperitoneal administration of luteolin for 16 days not only inhibited tumor growth, but also reduced the number of blood vessels in the tumor [
97].
Punicic acid, the major component of pomegranate seed oil (70%–80%), has been shown to possess anti-cancer effects on PCa. It inhibits cell growth of androgen-dependent LNCaP cells stimulated by DHT and inhibited DHT-stimulated androgen receptor nuclear accumulation as well as the expression of androgen receptor-dependent genes [
81]. These investigators also found that punicic acid induced apoptosis via a caspase-dependent pathway in LNCaP cells.
Recently, we showed that luteolin (L), ellagic acid (E) and punicic acid (P), individually and in combination, additively affect processes important for metastasis. L + E + P in equal amounts inhibits the growth of hormone-dependent and -independent PCa cells, their migration and their chemotaxis towards CXCL12, a factor that is important in PCa metastasis [
62]. The combination of these components also increases the expression of cell adhesion genes and decreases expression of genes involved in cell cycle control and cell migration. Furthermore, we found that L + E + P increases several well-known anti-invasive miRNAs, such as miR-200c and miR-335, while decreasing several oncogenic miRNAs, such as miR-21 and miR-29b. We have also shown similar anti-metastatic effects of L + E + P on breast cancer cells [
98].
Based on these results in cell culture, we investigated whether L + E + P inhibits PCa metastasis
in vivo. We used a SCID mouse model in which luciferase-expressing human PCa cells were injected ectopically in the region of the prostate. One advantage of this model is that tumor growth and metastasis can be monitored by bioluminescence imaging. We found that L + E + P significantly inhibited PC-3M-luc primary tumor growth and that none of the tumors treated with L + E + P metastasized. One disadvantage of using this model to study metastasis is the relative low metastasis incidence in untreated mice. However, it has been shown that inhibition of the PTEN/PI3K pathway combined with activation of the Ras/MAPK pathway promotes prostate cancer metastasis [
99]. Therefore, we further tested the effects of L + E + P on highly invasive Pten
−/−; K-ras
G12D PCa cells and found that L + E + P not only inhibited tumor growth but also inhibited lung and liver metastasis. L + E + P also significantly inhibited the CXCL12/CXCR4 axis for metastasis
in vivo, consistent with our findings
in vitro. In addition, we found that L + E + P inhibited angiogenesis in PC-3M-luc and Pten
−/−; K-ras
G12D tumors. We also showed that L + E + P decreased human endothelial cell migration and adhesion, disrupted endothelial tube formation and inhibited the production of the angiogenic factors IL-8 or VEGF by the tumors [
100]. The possible mechanisms of the anti-metastatic effects of L + E + P are summarized in . These results show that L + E + P can inhibit PCa progression/metastasis, indicating potential use of this combination of natural products for treatment of PCa in humans.
Possible mechanisms of the anti-metastatic effects of the combination of luteolin (L), ellagic acid (E) and punicic acid (P) (L + E + P). Possible mechanisms include increasing cell adhesion, decreasing cell migration and CXCL12 chemotaxis, inhibiting …
5. Clinical Trials of PE and/or PJ on PCa
To investigate the effects of PJ consumption on PCa progression in men, a phase II clinical trial for men with rising PSA after surgery or radiotherapy was conducted in 2006 [
101]. Patients were treated with 8 ounces of PJ daily until disease progression. During the trial, there were no serious adverse events reported and the treatment was well tolerated. Mean PSA doubling time significantly increased with treatment from a mean of 15 months at baseline to 54 months post-treatment (
p < 0.001). The investigators also found that PJ treatment suppressed cell proliferation and increased apoptosis in the prostate cancer cell line LNCaP. In addition, PJ treatment increased serum nitric oxide and reduced the oxidative state and sensitivity to oxidation of serum lipids in patients. No patients developed metastases during the period of the trial period.
In 2013, another phase II clinical trial of PCa patients with rising PSA received 1 g (comparable to about 8 oz of PJ) or 3 g of PE daily for up to 18 months. PSA doubling time lengthened more than 6 months from 11.9 to 18.5 months (
p < 0.001) with no significant difference between dose groups [
102]. Again, no patient developed metastases during the trial period. The statistically significant prolongation of PSA doubling time and the lack of metastatic progression in any of the patients in both of these studies, strongly suggests the potential of PJ for treatment of PCa.
Although extremely promising, a major drawback of these two clinical trials was the absence of a proper placebo control group. A recent randomized double blind study showed that men with PCa prior to radical prostatectomy were given PE daily for up to 4 weeks. No serious side effects were observed and the treatment was well tolerated. The level of 8-hydroxy-2-deoxyguanosine (8-OHdG), an oxidative stress biomarker, was compared between patients in treatment and placebo group. PE lowered the level of 8-OHdG but the difference was not statistically significant, suggesting the need for larger and longer studies in the future [
103].
More recently, results from a double-blind, placebo-controlled randomized trial using an oral capsule containing a blend of pomegranate, green tea, broccoli and turmeric showed that the supplement delayed PCa progression as indicated by slower increases in PSA levels. The median increase in PSA levels in the supplement group was 14.7% as compared to 78.5% in placebo group [
104], suggesting the great potential of the food supplement to prevent PCa progression.
6. Conclusions
In summary, the biological activity of pomegranate-derived products, especially the chemotherapeutic and chemopreventive properties, has been investigated in cell, animal and clinical studies. The findings discussed in this review show that pomegranate and its components interfere with multiple biological processes involved in tumor growth, angiogenesis and metastasis of PCa. Because many of the molecular mechanisms are shared by different types of cancers, and the fact that PE has been shown to be effective against breast, lung, colon and skin cancer [105] further enhances the therapeutic potential of PE. Therefore, further studies are warranted, including clinical trials with appropriate control groups using well-characterized and standardized amounts of PJ, PE and specific components as primary or adjuvant therapy in men with PCa. Many of the molecular mechanisms involved in the PJ/PE or L + E + P are amenable to drug treatment and to the development of small inhibitory molecules and therefore allow for combination therapy. Therefore, pomegranate and its components can potentially be used to prevent development and progression of PCa as well as other cancers. What is not known and is of great importance is whether the power of PJ/PE or L + E + P can be used as preventive therapies.