Prostate cancer (PCa) stands out as the most prevalent tumor in men aged 45 to 60 in highly developed countries, and its complexity arises from the interplay of genetic and environmental factors. This multifactorial disease involves non-modifiable factors like ethnicity, age, and hormonal status, alongside modifiable risk factors such as smoking, obesity, sedentary lifestyle, and poor dietary choices [1,2,3,4].
Genetic and Environmental Interactions:
The intricate interaction between genetic and environmental factors results in the dysregulation of genes controlling epigenetic processes, including histone modifications, DNA methylation, and non-coding miRNA .
Testosterone (T) and its derivative dihydrotestosterone (DHT) exert control over the prostate gland’s epithelial and stromal sections by binding to the androgen receptor (AR), regulating cell proliferation, differentiation, and metabolic-secretory functions [6,7].
Androgen Dependency in Prostate Cancer:
While androgens control the normal development of the prostate, the progression of prostate cancer can be both androgen-dependent and androgen-independent, impacting treatment approaches and outcomes . For less aggressive cases, active surveillance is recommended, whereas localized neoplasms may require androgen deprivation, surgery, or radiation, each with potential side effects. Metastatic disease often necessitates chemotherapy, extending survival compared to single treatments .
Therapeutic Challenges and Resistance:
Prostate cancer’s evolution towards therapy resistance is a significant challenge, often involving mutated androgen receptors and the emergence of androgen receptor variants and gene amplification [9,10,11,12,13]. Hormone refractoriness may lead to the neuroendocrine phenotype, associated with a poor prognosis and limited effective treatment strategies . Therefore, there is a critical need for novel therapeutic agents with enhanced efficacy and fewer side effects to complement traditional treatments.
The Role of Diet in Prostate Cancer Prevention:
Research consistently highlights the importance of diet in protecting against cardiovascular and neoplastic diseases. Fruit consumption, in particular, has been associated with the prevention of various cancers, including prostate cancer [15,16]. This has led researchers to explore the potential of natural compounds found in specific fruit varieties for their anticancer properties.
Poncirus trifoliata: A Potential Anticancer Agent:
The Rutaceae family, encompassing genera like Citrus and Poncirus, is a valuable source of flavonoids, limonoids, phenolic acids, and vitamin C, known for their antioxidant and anti-inflammatory properties crucial in cancer chemoprevention [17,18]. Poncirus trifoliata, commonly known as “trifoliate orange,” has gained attention due to its diverse biological activities, including anti-inflammatory, anti-bacterial, anti-anaphylactic, and hypoglycemic properties [19,20,21,22,23,18]. Moreover, P. trifoliata is recognized for its anticancer potential linked to its phytochemical compounds, such as phenolic acids, flavonoids, coumarins, alkaloids, triterpenoids, and sterols [19,24,25,26,27,28].
Unveiling Anticancer Mechanisms:
In a groundbreaking study, the present research marks the first investigation into the anticancer effects of P. trifoliata seed extract on human prostate cancer cells. The study focuses on the androgen receptor-positive LNCaP cell line, aiming to elucidate the molecular mechanisms underpinning the observed anticancer effects.
Discussion: Unveiling the Anticancer Potential of Poncirus trifoliata Seed Extract in Prostate Cancer
Prostate cancer (PCa) remains a significant global health concern, ranking as the second most common cancer and the sixth leading cause of male cancer-related deaths [31,32]. The etiology of prostate cancer involves a myriad of factors, both non-modifiable (such as age, ethnicity, and family history) and modifiable (including lifestyle habits, diet, and environmental exposures). Among these factors, the androgen receptor (AR) has emerged as a key player in the growth of both normal and malignant prostate epithelial cells .
The intricate relationship between AR and the expression of prostate-specific antigen (PSA) underscores their crucial role in the normal growth and differentiation of the prostate gland, as well as in various stages of cancer progression. Moreover, redox homeostasis imbalance and chronic inflammation have been implicated in promoting prostate carcinogenesis, prompting exploration into bioactive natural compounds from fruits and vegetables as potential strategies for delaying cancer progression. Notably, the highest concentrations of these bioactive compounds are found in peels and seeds [34,35].
Poncirus trifoliata Seed Extract: A Novel Anticancer Agent
While the potential bioactivity of Poncirus trifoliata (PT) seeds has been explored in various contexts, including the suppression of influenza virus replication and antioxidant properties [36,18], the present study represents the first investigation into the anticancer activity of PT seed extract. The chemical characterization of the extract revealed the presence of flavanones (naringin, neohesperedin, and narirutin) and the phenolic compound caffeic acid, compounds known for their diverse biological properties [18,37,38,39].
Flavanones as Potent Anticancer Agents: Unraveling Molecular Mechanisms
The identified flavanones, particularly naringin, neohesperidin, and narirutin, have demonstrated their ability to induce cell cycle arrest and apoptosis in various tumor cell lines [40,41,42]. Naringin, for instance, has been shown to inhibit cell survival, induce cell cycle arrest in the G1 phase, and promote apoptosis through the activation of various cellular pathways. Moreover, combining naringin with chemotherapeutic agents has shown synergistic effects, enhancing anticancer activity while reducing side effects . Similarly, narirutin has exhibited anti-tumor effects across different cancer types, including prostate cancer, by acting through various signal transduction pathways .
In the current study, P. trifoliata seed extract displayed a hormetic response, with low doses modestly stimulating cell proliferation, while higher concentrations led to a significant reduction in cell survival accompanied by morphological changes. The extract induced G0/G1 cell cycle arrest in LNCaP cells through up-regulation of the cyclin-dependent kinase inhibitor p27 and down-regulation of cyclin D1, highlighting its ability to regulate key cell cycle checkpoints.
Distinct Mechanisms of Action: Unraveling the Path to Apoptosis
Contrary to expectations, the observed cell cycle arrest induced by P. trifoliata seed extract did not involve the well-known tumor suppressor proteins p53 and p21waf. Instead, the extract increased p27 levels, inhibiting entry into the S phase and directing cells toward apoptosis. This shift towards apoptosis was further supported by the down-regulation of phospho-pRb, maintaining a proliferative block. The intricate network of cellular responses involving p27, Akt, and other signaling pathways underscores the complexity of P. trifoliata’s impact on LNCaP cells.
Apoptotic Signaling Pathways: Orchestrating Cellular Demise
The induction of apoptosis, a hallmark of anticancer activity, was evident in P. trifoliata-treated LNCaP cells. The Bcl-2 family proteins, crucial regulators of apoptosis, exhibited distinct responses. The extract reduced the levels of the anti-apoptotic protein Bcl-2 while increasing the expression of pro-apoptotic proteins Bax and Bad. The observed reduction in phospho-Bad (Ser112), a survival factor, further supported the pro-apoptotic effects of P. trifoliata seed extract. Additionally, DNA fragmentation, as evidenced by PARP cleavage and TUNEL assay, substantiated the apoptotic response.
MAPK Signaling: Navigating Cell Fate
Mitogen-activated protein kinase (MAPK) signaling plays a pivotal role in cell growth, differentiation, and apoptosis in response to various stimuli. P. trifoliata extract increased the levels of stress stimuli, such as p38 and JNK, while simultaneously reducing survival signaling mediated by ERK1/2, mTOR, and p70s6k. The diverse impact on kinase pathways elucidates the extract’s inhibitory activities on cell proliferation and apoptosis.
Targeting Prosurvival Pathways: A Multifaceted Approach
The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mTOR pathway, frequently activated in prostate cancer, plays a pivotal role in tumor formation, progression, and therapeutic resistance. Contrary to expectations, P. trifoliata extract did not down-regulate pro-survival pAKT; instead, it exhibited transient activation at short treatment times, followed by stable expression. This unique observation suggests that while P. trifoliata extract does not directly influence pAKT, it affects downstream signals such as mTOR and p70s6k.
Implications for Prostate Cancer Therapy: Future Directions
In conclusion, this study provides groundbreaking evidence of the anticancer effects of P. trifoliata seed extract on LNCaP prostate cancer cells. The observed inhibition of cell viability, induction of apoptosis, and modulation of crucial signaling pathways, including ERK1/2 MAPK and mTOR/P70S6K, underscores the potential of P. trifoliata as a therapeutic agent in prostate cancer.
The identification of specific components within the P. trifoliata seed extract with the most potent anti-proliferative and pro-apoptotic properties opens avenues for future research. This nuanced understanding may pave the way for the development of targeted therapies or the use of individual components in adjuvant treatments for prostate cancer. The complex interplay of molecular mechanisms uncovered in this study positions P. trifoliata as a promising candidate for further exploration in the pursuit of effective and targeted prostate cancer therapies.
As prostate cancer continues to be a significant health concern, the exploration of alternative therapeutic agents becomes imperative. P. trifoliata, with its rich phytochemical composition and demonstrated biological activities, emerges as a promising candidate. Understanding the molecular mechanisms behind its anticancer effects on prostate cancer cells may pave the way for innovative and effective treatment strategies with fewer side effects, offering hope to patients facing this challenging disease.
reference link :https://www.mdpi.com/1422-0067/24/22/16351