Herbs And Phytochemicals: Poncirus Trifoliata Seed Extract Induces Cell Cycle Arrest And Apoptosis In Androgen Receptor Positive LNCaP Prostate Cancer Cells

Herbs And Phytochemicals: Prostate cancer (PCa) stands as a formidable challenge to men's health globally, ranking as the second most prevalent cancer among males aged 45 to 60. The intricate tapestry of factors contributing to its incidence involves both genetic predisposition and modifiable environmental elements. As scientists delve deeper into the dynamics of prostate cancer, a groundbreaking Herbs And Phytochemicals study from the University of Calabria, Italy, brings to light the potential of Poncirus trifoliata (L.) Raf., commonly known as "trifoliate orange," and specifically its seed extract, as a novel therapeutic avenue for prostate cancer treatment.


 
Understanding Prostate Cancer Complexity
Prostate cancer is a multifactorial disease, where non-modifiable factors such as age, ethnicity, and hormonal status intersect with modifiable risk factors including smoking, obesity, sedentary lifestyle, and dietary habits. The delicate balance between genetics and environmental influences often leads to the deregulation of genes controlling crucial processes like epigenetics, involving histone modifications, DNA methylation, and non-coding miRNA.
 
In the intricate landscape of the prostate, androgen receptors (AR) play a pivotal role, controlling cell proliferation, differentiation, and metabolic-secretory functions. The progression of prostate cancer can manifest as androgen-dependent or androgen-independent, influencing the choice of treatment and the prognosis of the disease. Despite advancements in therapeutic approaches, prostate cancer often develops resistance to treatments over time, necessitating innovative solutions for effective management.
 
The Role of Diet in Prostate Cancer Prevention
Mounting evidence suggests that diet plays a pivotal role in protecting against various cancers, including prostate cancer. The consumption of fruits, in particular, has been associated with prevention and protection against different cancer types, such as breast, colon, pancreatic, lung, and prostate cancers. Within the Rutaceae family, which includes genera such as Citrus and Poncirus, lies a rich source of bioactive compounds like flavonoids, limonoids, phenolic acids, and vitamin C, known for their antioxidant and anti-inflammatory properties.
 
Poncirus trifoliata (L.) Raf., commonly referred to as "trifoliate orange," has a storied history in traditional medicine, where it has been used to treat gastrointestinal diseases, ulcers, gastritis, inflammation, and allergies. The focus of this article is a study conducted at the University of Calabria that explores the potential of Poncirus trifoliata seed extract in inhibiting the growth of prostate cancer cells.
 
Decoding the Chemical Profile of P. trifoliata Seed Extract
The study employed a meticulous extraction process, utilizing methanol as the solvent to extract bioactive compounds from Poncirus trifoliata seeds. Chemical analyses revealed the presence of three flavanones - naringin, neohesperedin, and narirutin - and the phenolic compound caffeic acid as the dominant cons tituents. Naringin emerged as the most abundant compound, setting the stage for a comprehensive exploration of these compounds' potential impact on prostate cancer cells.
 
Effects on Cell Viability and Morphological Changes
The research employed androgen-sensitive human prostate adenocarcinoma cells (LNCaP) to assess the impact of Poncirus trifoliata seed extract on cell viability. Results indicated a dose-dependent reduction in cell viability, with concentrations of 12.5 µg/mL and above demonstrating significant inhibitory effects. Morphological changes, including reduced cell volume and cytoplasmic extensions, were observed, underscoring the extract's potential to induce alterations in prostate cancer cells.
 
Cell Cycle Arrest and Apoptosis: Unraveling the Mechanisms
Flow cytometry analysis provided insights into the extract's impact on the cell cycle, revealing a dose-dependent increase in the percentage of cells in the G1 phase and a concomitant decrease in the S phase - a hallmark of cell cycle arrest at the G0/G1 phase. Western blot analysis further elucidated the molecular mechanisms behind this cell cycle arrest, identifying a reduction in cyclin D1, an up-regulation of the cyclin-dependent kinase inhibitor p27, and a decrease in phosphorylated retinoblastoma protein (pRb), collectively contributing to inhibiting cell cycle progression.
 
The study also investigated the impact of the extract on the androgen receptor (AR), a crucial player in prostate carcinogenesis. Poncirus trifoliata seed extract led to a decrease in AR expression, reinforcing its potential as a therapeutic agent against androgen-dependent prostate cancer.
 
Activation of the Intrinsic Apoptosis Pathway
To explore whether Poncirus trifoliata extract induced apoptosis in prostate cancer cells, the study assessed key proteins involved in the intrinsic pathway. Increased expression of pro-apoptotic proteins (Bax and Bad) and decreased levels of anti-apoptotic proteins (Bcl2 and Bid) were observed. Bad phosphorylation, crucial for cell survival, was reduced, indicating a shift towards apoptosis. Additionally, cleavage of poly (ADP-ribose) polymerase (PARP) and TUNEL assay results confirmed the occurrence of apoptotic cell death, particularly at higher extract concentrations.
 
Regulation of MAPK and mTOR/p70S6K Signaling Pathways
The study delved into the signaling pathways affected by Poncirus trifoliata seed extract, focusing on MAPK and mTOR/p70S6K. Activation of stress-activated MAPKs (p38 and c-Jun N-terminal kinase) was observed, while the pro-survival Akt/mTOR pathway exhibited transient activation followed by sustained reduction over time. This modulation of signaling pathways aligns with the extract's anti-proliferative and pro-apoptotic effects.
 
Discussion and Future Directions
The findings from this study underscore the potential of Poncirus trifoliata seed extract as a promising agent in prostate cancer treatment. The observed effects on cell viability, cell cycle progression, apoptosis induction, and signaling pathway modulation present a compelling case for further exploration. However, the road ahead involves in-depth studies to isolate and identify the specific components responsible for the extract's anti-neoplastic response.
 
Conclusion
In conclusion, Poncirus trifoliata seed extract emerges as a natural source with the potential to revolutionize prostate cancer treatment. Its multifaceted impact on cell viability, cell cycle progression, apoptosis induction, and signaling pathways sets the stage for future research aimed at isolating and harnessing the most potent components. As science delves deeper into the complexities of cancer biology, nature's bounty, exemplified by Poncirus trifoliata, may hold the key to innovative and effective cancer therapies. This study not only sheds light on the promising anti-cancer properties of P. trifoliata seed extract but also paves the way for future investigations in the realm of phytochemical-based cancer therapeutics. As we navigate the uncharted territories of cancer research, Poncirus trifoliata seed extract stands as a beacon of hope in the quest for novel, effective, and nature-inspired approaches to prostate cancer treatment.
 
The study findings were published in the peer reviewed International Journal of Molecular Sciences.
https://www.mdpi.com/1422-0067/24/22/16351
 
For the latest on Herbs And Phytochemicals, keep on logging to Thailand Medical News.
 
Read Also:
Phytotherapeutic effects of the fruits of Poncirus trifoliata (L.) Raf. on cancer, inflammation, and digestive dysfunction
https://onlinelibrary.wiley.com/doi/10.1002/ptr.6008
 
Inhibition of colon cancer cell growth and antioxidant activity of bioactive compounds from Poncirus trifoliata (L.) Raf.
https://www.sciencedirect.com/science/article/abs/pii/S0968089607003719
 
Prokinetic activity of an aqueous extract from dried immature fruit of Poncirus trifoliata (L.) Raf.
https://pure.ewha.ac.kr/en/publications/prokinetic-activity-of-an-aqueous-extract-from-dried-immature-fru
 
Antiviral activity of Poncirus trifoliata seed extract against oseltamivir-resistant influenza virus
https://link.springer.com/article/10.1007/s12275-018-8222-0
 
Autophagic Cell Death by Poncirus trifoliata Rafin., a Traditional Oriental Medicine, in Human Oral Cancer HSC-4 Cells
https://www.hindawi.com/journals/ecam/2015/394263/

Poncirus trifoliata Rafin. induces the apoptosis of triple-negative breast cancer cells via activation of the c-Jun NH(2)-terminal kinase and extracellular signal-regulated kinase pathways
https://phcog.com/article/view/2015/11/44s1/s237-s243
 
Protective effects of neohesperidin and poncirin isolated from the fruits of Poncirus trifoliata on potential gastric disease
https://onlinelibrary.wiley.com/doi/10.1002/ptr.2840
 
Poncirus Trifoliata (L.) Raf. Extract Inhibits the Development of Atopic Dermatitis-like Lesions in Human Keratinocytes and NC/Nga mice
https://www.medsci.org/v16p1116.htm
 
Neohesperidin Induces Cellular Apoptosis in Human Breast Adenocarcinoma MDA-MB-231 Cells via Activating the Bcl-2/Bax-mediated Signaling Pathway
https://journals.sagepub.com/doi/abs/10.1177/1934578X1200701116
 
Anti-Obesity and Hypoglycemic Effects of Poncirus trifoliata L. Extracts in High-Fat Diet C57BL/6 Mice
https://www.mdpi.com/1420-3049/21/4/453
 
Long-term administration of an aqueous extract of dried, immature fruit of Poncirus trifoliata (L.) Raf. suppresses body weight gain in rats
https://www.sciencedirect.com/science/article/abs/pii/S0378874109005212