Apigenin role as cell-signaling pathways modulator: implications in cancer prevention and treatment

The scientific paper Apigenin Role as Cell-Signaling Pathways Modulator: Implications in Cancer Prevention and Treatment by Javed et al. investigates the anticancer properties of apigenin, a natural compound commonly found in fruits, vegetables, and herbs. The authors review research on how apigenin can target and modulate key molecular pathways involved in cancer cell growth, survival, and spread, such as the TRAIL, PI3K/Akt/mTOR, JAK/STAT, Wnt/β-catenin, and MAPK pathways. By interacting with these pathways, apigenin has the potential to inhibit tumor growth, promote apoptosis (programmed cell death), and prevent cancer metastasis. The paper also explores the use of nano-formulations of apigenin to enhance its bioavailability and therapeutic effects, positioning apigenin as a promising candidate for cancer prevention and treatment.

Cancer is a complex disease caused by a combination of genetic mutations and environmental factors that lead to uncontrolled cell growth and spread. Current cancer treatments, like chemotherapy and radiation, can have severe side effects and don't always work for all patients. This has sparked interest in natural compounds that could provide safer and more effective alternatives.

One such compound is apigenin, a naturally occurring flavonoid found in fruits, vegetables, and herbs like parsley, celery, and chamomile. Apigenin has been shown to interfere with various signaling pathways that cancer cells use to grow , divide, and evade the body's natural defenses. This research explores how apigenin can help in preventing and treating different types of cancer by targeting these pathways.

The authors conducted a comprehensive review of existing studies to analyze apigenin's role in cancer therapy . They focused on apigenin's effects on five major signaling pathways commonly involved in cancer progression: TRAIL, PI3K/Akt/mTOR, JAK/STAT, Wnt/β-catenin, and MAPK. In addition, they examined apigenin's interactions with microRNAs (miRNAs), which are small molecules involved in regulating gene expression and are critical players in cancer development. The authors also evaluated how advancements in nano-formulations could improve the delivery and effectiveness of apigenin in cancer treatment.

The review gathered data from in-vitro (cell culture) and in-vivo (animal model) studies across various types of cancers, including prostate, breast, lung, and colorectal, to highlight apigenin's multi-faceted role in cancer therapy. They aimed to provide a clearer understanding of how apigenin could be developed into a viable treatment for human cancer patients.

Apigenin enhances the TRAIL (TNF-related apoptosis-inducing ligand) pathway , which plays a critical role in activating apoptosis, or programmed cell death, in cancer cells. Many cancer cells evade apoptosis by overproducing anti-apoptotic proteins, such as BCL2 and XIAP. Apigenin helps overcome this resistance by lowering the levels of these proteins and boosting death receptors like DR5, which promotes apoptosis.

For example, in colon cancer cells (HCT-116), apigenin increased the expression of BID/BAX and activated caspase-3, caspase-8, and caspase-9, essential proteins in the apoptotic process. The study highlights that "apigenin prevents ANT-2 mediated deactivation of the DISC complex and promotes apoptosis in cancer cells."

The PI3K/Akt/mTOR pathway is a vital signaling cascade that controls cell growth, metabolism, and survival. Abnormal activation of this pathway is a hallmark of many cancers. Apigenin has been shown to inhibit this pathway by blocking the phosphorylation of Akt, a key protein that promotes cancer cell survival.

It also upregulates tumor suppressor proteins like FOXO3a, which helps induce growth arrest in cancer cells. According to the paper, apigenin "prevents PI3K from interacting with Akt and disrupts the activation of the mTORC2 complex, a key player in cancer cell proliferation." By preventing this interaction, apigenin slows down tumor growth and can lead to cancer cell death. This effect has been observed in several cancer types, including breast, lung, and prostate cancers.

The JAK/STAT signaling pathway controls processes like immune response, cell division, and apoptosis. This pathway becomes hyperactive in many cancers, allowing tumors to grow uncontrollably. Apigenin was found to inhibit the phosphorylation of JAK2 and STAT3 , two proteins that are critical for activating cancer-promoting genes. By blocking these proteins, apigenin reduces the expression of VEGF and MMPs, which are involved in angiogenesis (the formation of new blood vessels) and tumor invasion.

The study notes that in breast cancer cell lines (MDA-MB-453), "apigenin successfully reduced the expression of STAT3 and STAT5, preventing tumor growth and proliferation." This inhibition prevents cancer cells from growing and spreading to other parts of the body.

The Wnt/β-catenin pathway is crucial for regulating cell division and maintaining tissue homeostasis. In many cancers, including colorectal cancer, this pathway is abnormally activated, leading to uncontrolled cell growth. Apigenin has been shown to inhibit the accumulation of β-catenin in the cytoplasm and prevent its translocation to the nucleus, where it can activate genes involved in tumor growth.

This effect is dose-dependent, meaning higher concentrations of apigenin result in greater suppression of β-catenin. Additionally, apigenin promotes the expression of E-cadherin, a protein that helps cells stick together and prevents them from spreading. The research emphasizes that "apigenin attenuates the Wnt/β-catenin signaling pathway, reducing cancer cell migration and invasion."

The MAPK signaling pathway is essential for controlling cell proliferation, differentiation, and death. It consists of several proteins, including ERK, c-JUN, and p38, that are often overactive in cancer cells. Apigenin has been found to inhibit the activation of ERK1/2, which in turn suppresses tumor growth.

In melanoma and lung cancer cell lines, apigenin reduced the levels of p-ERK and p-Akt, promoting apoptosis and reducing the cells' ability to invade surrounding tissues. The study also mentions that in particular prostate cancer models, apigenin targeted the IGF/IGFBP-3 axis, leading to downregulating p-Akt and suppressing the ERK signaling pathway.

MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression, and their abnormal expression is linked to cancer. Apigenin has been found to influence both tumor-promoting and tumor-suppressing miRNAs, enhancing its anticancer effects. For example, apigenin increases the expression of miR-101, a tumor-suppressing miRNA, reducing the expression of NRF2, a protein involved in drug resistance.

This makes cancer cells more sensitive to chemotherapy drugs like doxorubicin. The paper notes that "apigenin in combination with miR-520b mimics sensitized hepatocellular carcinoma cells to doxorubicin," suggesting that apigenin could be useful in overcoming drug resistance in cancer therapy.

One of the main challenges with using apigenin as a cancer treatment is its poor bioavailability. It is not very soluble in water, and the body breaks it down quickly. However, researchers have developed nano-formulations of apigenin, which help deliver it more effectively to cancer cells. For example, apigenin-loaded gold nanoparticles (ap-AuNPs) have been shown to reduce cancer cell growth and even inhibit the formation of new blood vessels in skin cancer models.

Another promising development is the use of bovine serum albumin nanoparticles (BSA-Api-NPs), which have been effective in reducing lung injury and inflammation and have potential applications for lung cancer treatment. The paper mentions that these nano-formulations help "increase apigenin's retention time in the body, allowing for targeted cancer therapy with reduced side effects."

The research highlights apigenin's significant potential as a natural cancer therapy. By targeting multiple signaling pathways that are essential for cancer cell survival and growth, apigenin could provide a multi-faceted approach to cancer treatment. It not only directly induces cancer cell death but also makes cancer cells more sensitive to existing treatments like chemotherapy. This makes apigenin a promising candidate for combination therapies, where it could be used alongside standard treatments to improve patient outcomes.

One of the most exciting aspects of apigenin's potential is the development of nano-formulations that improve its effectiveness. These advancements could make apigenin a more viable option in clinical settings, offering better-targeted treatments with fewer side effects. The study suggests that "nano-formulations could solve the problem of apigenin's poor bioavailability, making it a more powerful tool in cancer therapy." However, the authors stress that more research, particularly in human trials, is needed to confirm these findings and to develop apigenin-based treatments that can be safely used in humans.

Apigenin offers considerable potential as a cancer-fighting compound. Its ability to influence critical pathways that control cancer cell growth, survival, and metastasis makes it a strong candidate for future cancer therapies. Though current research shows its effectiveness in preclinical models, further studies are needed to fully harness apigenin's therapeutic benefits, particularly in human trials. The use of nano-formulations may overcome the challenges of poor bioavailability, making apigenin a promising addition to the natural compounds being explored for cancer treatment.