Cancer Chemoprevention Research Articles

Enhanced Chemoprevention of Prostate Cancer by Combining Arctigenin with Green Tea and Quercetin in Prostate-Specific Phosphatase and Tensin Homolog Knockout Mice.

The low bioavailability of most phytochemicals limits their anticancer effects in humans. The present study was designed to test whether combining arctigenin (Arc), a lignan mainly from the seed of Arctium lappa, with green tea (GT) and quercetin (Q) enhances the chemopreventive effect on prostate cancer. We performed in vitro proliferation studies on different cell lines. We observed a strong synergistic anti-proliferative effect of GT+Q+Arc in exposing androgen-sensitive human prostate cancer LNCaP cells. The pre-malignant WPE1-NA22 cell line was more sensitive to this combination. No cytotoxicity was observed in normal prostate epithelial PrEC cells. For an in vivo study, 3-week-old, prostate-specific PTEN (phosphatase and tensin homolog) knockout mice were treated with GT+Q, Arc, GT+Q+Arc, or the control daily until 16 weeks of age. In vivo imaging using prostate-specific membrane antigen (PSMA) probes demonstrated that the prostate tumorigenesis was significantly inhibited by 40% (GT+Q), 60% (Arc at 30 mg/kg bw), and 90% (GT+Q+Arc) compared to the control. A pathological examination showed that all control mice developed invasive prostate adenocarcinoma. In contrast, the primary lesion in the GT+Q and Arc alone groups was high-grade prostatic intraepithelial neoplasia (PIN), with low-grade PIN in the GT+Q+Arc group. The combined effect of GT+Q+Arc was associated with an increased inhibition of the androgen receptor, the PI3K/Akt pathway, Ki67 expression, and angiogenesis. This study demonstrates that combining Arc with GT and Q was highly effective in prostate cancer chemoprevention. These results warrant clinical trials to confirm the efficacy of this combination in humans.

Utilizing Human Genetics to Develop Chemoprevention for Cancer-Too Good an Opportunity to be Missed.

Large-scale genetic studies are reliably identifying many risk factors for disease in the general population. Several of these genetic risk factors encode potential drug targets, and genetics has already helped to introduce targeted agents for some diseases, an example being lipid-lowering drugs to reduce the incidence of cardiovascular disease. Multiple drugs have been developed to treat cancers based on somatic mutations and genomics, but in stark contrast, there seems to be a reluctance to use germline genetic data to develop drugs to prevent malignancy, despite the large numbers of people who could benefit, the potential for lowering cancer rates, and the widespread current use of non-pharmaceutical measures to reduce cancer risk factors such as tobacco, alcohol, and infectious diseases. We argue that concerted efforts for cancer prevention based on genetics, including genes influenced by common polymorphisms that modulate cancer risk, are urgently needed. There are enormous, yet underutilized, opportunities to develop novel targeted agents for chemoprevention of cancer based on human germline genetics. Such efforts are likely to require the support of a dedicated funding program by national and international agencies. See related commentary by Winham and Sherman, p. 13.

Prevention of Urinary Bladder Cancer - The Trail Less Trodden

Though the pathogenesis of urinary bladder cancer is now well known, the exact aetiology of this disease is still in darkness. The advances in the management of bladder cancer have focused only on early identification and treatment of the illness since stage of disease at the time of diagnosis is a critical factor determining the outcome of treatment. Though primary chemoprevention of any disease aims at decreasing the incidence, secondary objectives like reducing treatment-related adverse events, cutting down the cost of treatment and bringing down the mortality due to the disease are also of concern. Chemoprevention of bladder cancer is a path less trodden. The primary reason for this lacunae has been the lack of identification of specific agents useful for this purpose. This article reviews the experimental and epidemiological data available from 1998 to 2024 on the effectiveness and safety of various nutritional and other agents proposed to be useful for bladder cancer chemoprevention to reduce the incidence of this cancer and/or slow down the disease progression. The results of the review show that no single agent has been categorically proved to be the best for chemoprevention of bladder cancer as of now. It may be ideal for patients who are at higher risk of contracting bladder cancer to adopt feasible chemopreventive measures which could potentially retard the onset or further course of disease including life style modifications and quitting smoking habits.

Role of kiwifruit in the inhibition of carcinogenesis: Proof-of-concept from cell culture studies and xenografted mice

Abstract Kiwifruit initially gained the limelight because of its remarkable health benefits. Still, its mechanistic involvement in the chemoprevention of carcinogenesis and metastasis has enabled researchers to evaluate anticancer and anti-metastatic effects in cell culture studies and xenografted mice. Interdisciplinary researchers have witnessed groundbreaking discoveries related to the pharmacological targeting of oncogenic proteins by kiwifruit in xenografted mice. Therefore, kiwifruit extracts, bioactive molecules, and nanovesicles have been investigated in different cancers. Although its importance was previously unrecognized, kiwifruit-derived nanovesicles are expected to showcase an increasingly prominent role in the chemoprevention of cancer as strategically preferable delivery vehicles. Accumulating evidence has started unraveling pleiotropic regulation of protein networks and biochemical modifications by kiwifruit in various cancers. Ubiquitination, autophagy, and mitophagy are some of the critical pathways reported to be regulated by kiwifruit extracts and bioactive chemicals. Nevertheless, realistically, this is the beginning of a new era in the context of mechanistic regulation of a myriad of cell signaling cascades in the prevention of carcinogenesis and metastasis.

Heat shock cognate 70 protein is a novel target of nobiletin and its colonic metabolites in inhibiting colon carcinogenesis.

Nobiletin (NBT) is a unique flavonoid mainly found in citrus fruits and has been reported to inhibit colon carcinogenesis in multiple rodent models. However, the direct molecular targets of NBT are unknown, which greatly limits its utilization in cancer prevention and treatment. In this study, using affinity chromatography, proteomics, computer modeling and various biochemical analyses, for the first time we identified HSC70 as a direct protein target of NBT in colon cancer cells. Moreover, NBT bound to HSC70 at its ATP-binding site and inhibited its ATPase activity. Importantly, our results also demonstrated that the major colonic metabolites of NBT (generated in the colon of NBT-fed mice) produced similar inhibitory effects against HSC70-mediated pro-carcinogenic events to those of NBT. Overall, our results provide a solid basis to further investigate the implication of the interaction between NBT/NBT metabolites and HSC70 in cancer chemoprevention.

Potential of covalently linked tamoxifen hybrids for cancer treatment: recent update.

Cancer is a complex disease and the second leading cause of death globally, and breast cancer is still a leading cause of cancer death in women. Tamoxifen is the most commonly used drug for breast cancer (ER-positive) treatment and chemoprevention, saving the lives of millions of patients every year. In addition, the tamoxifen template has been explored extensively for the development of selective estrogen receptor modulators (SERMs) applicable in breast cancer, osteoporosis, and postmenopausal symptom treatment. Numerous anticancer drugs, including tamoxifen, are in use, but the complexity and heterogeneous nature of cancer complicate the effect of conventional targeted drugs, leading to adverse reactions and resistance. One of the significant approaches to overcome these shortcomings is drug hybrids, generated by covalently linking two or more active pharmacophores. These drug hybrids are remarkably effective in acting on multiple drug targets with higher selectivity and specificity. In recent years, several tamoxifen hybrids have been discovered as potential candidates for cancer treatment. The review highlights the recent progress in developing anticancer hybrids, including organometallic, fluorescent, photocaged, and novel ligand-based tamoxifen hybrids. It also demonstrates the significance of merging various pharmacophores with tamoxifen to produce more potent, precise, and effective anticancer agents. The study offers valuable knowledge to researchers working on cancer research with the hope of enhancing drug potency and reducing drug toxicity to improve cancer patients' lives.

Concise synthesis of deuterium-labelled proanthocyanidin metabolite 5-(3',4'-dihydroxyphenyl)-γ-valerolactone as an analytical tool.

Deuterated proanthocyanidin metabolite 5-(3',4'-dihydroxyphenyl)-γ-valerolactone has been successfully produced. This metabolite is responsible for several proanthocyanidin protective effects in the field of cancer chemoprevention, skin wrinkle-prevention, and antimicrobials. The synthetic approach applied employs a short reaction sequence and allows the incorporation of four deuterium atoms on non-exchangeable sites, making it an attractive strategy to produce a stable isotopically labeled internal standard for quantitative mass spectrometry isotope dilution-based methods, as demonstrated by developing an LC-MS/MS method to quantify DHPV in urine samples. Overall, this efficient synthesis provides a valuable analytical tool for the study of the metabolic conversion of proanthocyanidins thus helping to investigate the biological effect and establishing the active dose of the key catabolite 5-(3',4'-dihydroxyphenyl)-γ-valerolactone.

Ciljanje onkogenih puteva posredstvom laktoferina u hemioprevenciji raka i dopunskoj terapiji - od mehanističkih uvida do kliničkih ispitivanja

Genetic, genomic and proteomic analyses of cells, tissues and body fluids have generated a wealth of precious information about the intricate mechanisms which underlie carcinogenesis and metastasis. Lactoferrin, a multifunctional cationic glycoprotein, has attracted widespread appreciation because of its characteristically novel properties for cancer chemoprevention. Tumor microenvironment is a highly complicated and sophisticated ecosystem, significantly reshaped by a wide variety of treatment regimes. Therefore, lactoferrin-mediated immunostimulatory role reshapes tumor microenvironment and inhibits cancer progression. There is sufficient experimental evidence related to immunostimulatory ability of lactoferrin in tumor microenvironment. Different clinical trials have been conducted for the evaluation of clinical efficacy of lactoferrin in different cancer patients. It is necessary to carefully interpret the clinical evidence and identify the major gaps in our understanding related to the selection of group of cancer patients likely to benefit the most from the combinatorial treatment regime comprised of lactoferrin and chemotherapeutic drugs. Moreover, lack of efficacy should be analyzed by a team of interdisciplinary researchers for a broader and comprehensive understanding of the mechanisms underlying treatment failure.

Synthesis and characterization of Fe3O4@SiO2@PDA@Ag core–shell nanoparticles and biological application on human lung cancer cell line and antibacterial strains

Novel magnetic and metallic nanoparticles garner much attention of researchers due to their biological, chemical and catalytic properties in many chemical reactions. In this study, we have successfully prepared a core–shell Fe3O4@SiO2@PDA nanocomposite wrapped with Ag using a simple synthesis method, characterised and tested on small cell lung cancer and antibacterial strains. Incorporating Ag in Fe3O4@SiO2@PDA provides promising advantages in biomedical applications. The magnetic Fe3O4 nanoparticles were coated with SiO2 to obtain negatively charged surface which is then coated with polydopamine (PDA). Then silver nanoparticles were assembled on Fe3O4@SiO2@PDA surface, which results in the formation core–shell nanocomposite. The synthesised nanocomposite were characterized using SEM-EDAX, dynamic light scattering, XRD, FT-IR and TEM. In this work, we report the anticancer activity of silver nanoparticles against H1299 lung cancer cell line using MTT assay. The cytotoxicity data revealed that the IC50 of Fe3O4@SiO2@PDA@Ag against H1299 lung cancer nanocomposites cells was 21.52 µg/mL. Furthermore, the biological data of nanocomposites against Gram-negative ‘Pseudomonas aeruginosa’ and Gram-positive ‘Staphylococcus aureus’ were carried out. The range of minimum inhibitory concentration was found to be 115 µg/mL where gentamicin was used as a standard drug. The synthesized AgNPs proves its supremacy as an efficient biomedical agent and AgNPs may act as potential beneficial molecule in lung cancer chemoprevention and antibacterial strains.

Current stage of preclinical and clinical development of guggulsterone in cancers: Challenges and promises.

Throughout human history, the utilization of medicinal herbs has been recognized as a crucial defense against various ailments, including cancer. Natural products with potential anticancer properties, capable of inducing apoptosis in cancer cells, have garnered substantial attention. One such agent under investigation is guggulsterone (GS), a phytosterol derived from the gum resin of the Commiphora mukul tree. This review aims to provide a comprehensive summary of recent studies elucidating the anticancer molecular mechanisms and molecular targets of GS, guiding future research and potential applications as an adjuvant drug in cancer therapy. Recent in vivo and in vitro studies have explored the biological activities of the active ingredients in Commiphora mukul. Specifically, GS emerges as a potential cancer chemopreventive and therapeutic agent. The investigations delve into the impact of GS on constitutively activated survival pathways, including Janus kinase/signal transducer and activator of transcription (JAK/STAT), nuclear factor-kappa B (NF-kB), and PI3-kinase/AKT signaling pathways. These pathways regulate antiapoptotic and proinflammatory genes, exerting control over growth and inflammatory responses. The findings highlight the potential of GS in disrupting survival pathways crucial for cancer cell viability. The inhibition of JAK/STAT, NF-kB, and PI3-kinase/AKT signaling pathways positions GS as a promising candidate for cancer therapy. The review synthesizes evidence from diverse studies, underscoring the multifaceted biological activities of GS in cancer prevention and treatment. To advance our understanding, future clinical and translational studies are imperative to determine effective doses in humans. Additionally, there is a need for the development of new pharmaceutical forms of GS to optimize therapeutic effects. This comprehensive review provides a foundation for ongoing research, offering insights into the potential of GS as a valuable addition to the armamentarium against cancer.

Comparative Anticancer Potential of Green Tea Extract and Epigallocatechin-3-gallate on Breast Cancer Spheroids.

Despite advances in diagnosis and therapy, breast cancer remains the leading cause of death in many countries. Green tea (GT) has been proposed to play a crucial role in cancer chemoprevention. Although extensive research has been conducted on GT phytochemicals, most experimental studies concentrate mainly on commercial formulations or isolated catechins. This study presents a comparative investigation into the anticancer properties of green tea extract (GTE) and epigallocatechin-3-gallate (EGCG) in a three-dimensional (3D) MCF-7 breast cancer cell culture. MCF-7 spheroids were exposed to GTE or EGCG, and effects on 3D culture formation, growth, cell viability, and migration were examined. GTE inhibits cell migration and the formation of breast cancer spheroids more effectively than EGCG, while inducing more pronounced morphological changes in the spheroids' structure. These findings suggest that the food matrix improves GTE effects on breast cancer spheroids, supporting the hypothesis that a mixture of phytochemicals might enhance its anticancer potential.

Contraception as chemoprevention of ovarian cancer in BRCA1 and BRCA2 women.

Ovarian cancer is the seventh most common cancer in women in the world, with an estimated worldwide mortality of over 207'000 women every year. This cancer, due to the current lack of adequate screening techniques, is commonly diagnosed late and has a poor prognosis. The oral contraceptive pill is considered the most effective prevention strategy for ovarian cancer in the general population, being associated with a decreased incidence while also having a substantial positive impact on the mortality rate, which is reduced by up to 50%. BRCA1 and BRCA2 germline mutated women have an augmented risk of ovary and breast cancer: despite international guidelines that consider prophylactic surgery as the gold standard for ovarian cancer prevention, there are currently no effective non-invasive preventive methods. In BRCA1\2 mutated patients, clinicians should weigh the benefits of contraceptive pills against the risk of long-term thromboembolic side effects and hormonal malignancies such as breast and cervical cancer. A multidisciplinary team should counsel patients on the most appropriate risk-reduction strategy tailored to their needs and expectations, proposing the oral contraceptive pill to selected patients after balancing the risks of adverse effects and the benefits on both contraception and chemoprevention.

Vanadium oxide 3- methoxy salen, a synthetic biologically active complex against HeLa and McCoy cell lines

Background: Vanadium is an essential dietary microelement that plays a key role in metabolic pathways and has anti-neoplastic effects. In this regard, vanadium oxide 3-methoxy salen complex was produced and its anticancer effects were evaluated against HeLa and McCoy cell lines.
 Methods: Schiff bases produced from equivalents of Vanadyl acetylacetonate [VO(acac)2] in methanol were used to make a vanadium oxide 3-methoxy salen complex. Then, The antioxidant property of compound, cell viability and cytotoxicity assay, DNA fragmentation analysis and determination of the apoptosis pathway genes were evaluated.
 Results: The result showed that the compound with an RC50 value of 126.3 µM demonstrated considerable free radical scavenging activity. The combination strongly suppressed the viability and proliferation of HeLa and McCoy cell lines in a dose-dependent manner, with IC50 values of 213 µM and 175 µM, respectively. When the viability and cytotoxicity values of the treated cells were compared, it was discovered that the cells had died of apoptosis, which was validated by DNA fragmentation analysis. Capspase 3, Bcl2 antagonist/killer, and Bcl2 associated X protein (Bax) gene expression levels all increased significantly in a quantitative investigation of apoptotic pathway genes, with 2-CT values of 2.36, 2.63, and 3.18, respectively.
 Conclusion: In HeLa and McCoy malignant cell lines, lower quantities of the complex caused programmed cell death. This potential of complex can be used in cancer chemoprevention and cancer therapy.

Cytotoxic Activities, Determining Toxin, and Molecular Docking of Ovary Pufferfish (Tetraodon leiurus) in Singkarak Lake as Cancer Chemoprevention Candidate

The primary toxin class discovered in freshwater pufferfish is a category of neurotoxins called PSTs (Paralytic shellfish toxins) and pufferfish toxin has been observed to have biological, biochemical, and cytotoxic effects on cancer cell lines. Therefore, it is crucial to determine the cytotoxic activity, toxins present in the ovary of T. leiurus, and interaction between ligand (toxin compound) and receptors test. This study used the MTT method in the T47D cell lines, liquid chromatograph-tandem mass spectrometry (LC-MS/MS), and analysis of the molecular interaction using molecular docking. The ovary of T. leiurus had cytotoxicity on the T47D cell, having an IC50 value of 229.535 μg/ml, and generated a chromatogram with a retention duration of 1.25 min that was similar to the Decarbamoylneosaxitoxin (dcNEO) standard solution. In molecular interactions between the dcNEO ligand to receptors, the lowest ΔG value was -9.29 kcal/mol at the Nav 1.7 receptor, and the lowest KI value was 1.23 µM at the Mcl-1 receptor. These findings indicate that the ovary of T. leiurus is cytotoxic to the T47D cell line and contains dcNEO toxin. It is more stable for the dcNEO ligand to engage with the Nav 1.7 receptor than with other receptors, and it inhibits the Mcl-1 receptor more potently than with other receptors. These findings indicate that the ovary of T. leiurus may be chemotherapy for the prevention of cancer strategy.

Bioactive Natural Products for Breast Cancer Chemoprevention and Treatment

Background: In addition to being one of the deadliest tumors, breast cancer is also one of the most difficult to cure. Due to the serious side effects of current breast cancer treatments and the rise in drug resistance, current drugs are losing their effectiveness. Potential Natural Bioactives: Bioactive natural compounds target various pathophysiological pathways involved in the development and progression of cancer and hence have the ability to prevent both the growth of breast cancer and the advancement of metastatic disease concurrently. : Natural anticancer compounds have been shown to be effective, complementary treatment may be of great assistance in this case. Clinical Outcomes: Nutraceuticals and popular folk remedies may provide benefits over manufactured pharmaceuticals since they have fewer side effects and less toxicity in both in vitro and in vivo studies. A variety of natural compounds have been shown to reduce the aggressiveness of breast cancer, inhibit the growth of malignant cells, and alter the pathways involved in cancer development and progression. Either by directly affecting certain biological targets, such genes, or by indirectly stabilising conjugates that have an impact on metabolic processes, natural compounds called phytochemicals can enhance human health. Mechanistic Pathways: There are many promising bioactive natural products that can be used to treat breast cancer, including those that inhibit aromatase activity, target HIF-1 signaling, inhibit cytoplasmic signaling, modulate epigenetic regulation, modulate estrogen signaling pathways, or work in chemosensitivity/adjuvant therapy (such as resveratrol, epigallocatechin-3-gallate, and eugenol).

Microbiomes in Post–Digital Rectal Exam Urine Samples are Linked to Prostate Cancer Risk

Abstract Purpose: Bacterial species including Cutibacterium acnes (C. acnes) have been associated with different inflammatory and neoplastic conditions in prostate cancer (PCa) tissue samples, but their clinical impact is unknown. Using next-generation sequencing (NGS)–based clinical reports, we investigated the differential abundance and incidence of microbiomes in post–digital rectal exam (DRE) urine samples from patients with PCa and a matched control group at low risk of PCa. Materials and Methods: A total of 200 post-DRE urine samples were analyzed, 100 from patients with histopathologically confirmed PCa and 100 from men at very low risk of PCa with PSA <1.5 ng/mL as controls. Bacterial and fungal communities were characterized by NGS of 16S and internal transcribed spacer (ITS) loci, respectively, with species' relative abundances provided on physicians' clinical reports. The differential abundance and incidence of species between cancer and control groups were evaluated. Results: Microbes were reported in 39% and 56% of PCa and control group samples, respectively. C. acnes had a significantly higher relative abundance in patients with PCa vs controls (P < .05), and C. acnes incidence rates were also nominally higher in patients with PCa as compared with controls (12.82% and 7.27%, respectively). By contrast, Finegoldia magna (F. magna) had a significantly higher relative abundance (P < .05) and incidence rate (P < .05) in controls as compared with patients with PCa. Conclusions: C. acnes was among the most prevalent bacterial species in PCa urine samples. F. magna identified in the low-risk group is responsible for production of equol, a soy metabolite associated with lowering risk of PCa, suggesting a role in prostate cancer chemoprevention.

Novel sulindac derivatives for colorectal cancer chemoprevention that target cGMP phosphodiesterases to suppress Wnt/β-catenin transcriptional activity

<p class="MsoNormal" style="margin-top: 6pt; line-height: 13pt; text-align: justify;"><span lang="EN-US" style="font-size: 10pt; font-family: arial, helvetica, sans-serif;">Approximately 28 million individuals in the United States face the risk of developing precancerous colonic adenomas (polyps) and potentially progressing to colorectal cancer (CRC). While a promising strategy for CRC prevention involves pharmacological intervention, such as cancer chemoprevention or interception, currently, there are no FDA-approved drugs capable of preventing the formation or progression of adenomas to adenocarcinoma. Numerous clinical, epidemiological, and preclinical studies have offered compelling evidence supporting the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) in CRC chemoprevention. However, the prolonged use of NSAIDs is not FDA-approved due to potential life-threatening toxicities resulting from cyclooxygenase (COX) inhibition and the depletion of physiological prostaglandins. Despite indications that the COX inhibitory activity of NSAIDs may not be essential for their antineoplastic effects, the absence of a well-defined target impeded the development of derivatives that do not inhibit COX. Earlier research suggests that the inhibition of cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) may be responsible, at least in part, for the antineoplastic activity of the NSAID sulindac. This could potentially offer a novel target for CRC chemoprevention. To identify the cGMP PDE isozyme(s) contributing to the antineoplastic activity of sulindac, we synthesized a chemically diverse library of over 1500 compounds, all sharing the indene scaffold of sulindac. Subsequently, we screened these compounds for their impact on cancer cell growth and PDE inhibitory activity. From this screening, a series of lead compounds emerged. These compounds lacked COX-1 and COX-2 inhibitory activity, surpassing sulindac in potency to inhibit CRC cell growth. Importantly, they demonstrated greater selectivity by not affecting normal cell growth. Through chemical optimization, we identified several development candidates that selectively inhibit PDE5 and/or PDE10. These compounds activate cGMP/PKG signaling, suppressing Wnt/β-catenin transcription. This action counters the growth advantages resulting from APC or CTNNB1 mutations, which are responsible for most human CRCs. This review delves into the scientific literature supporting PDE5 and/or PDE10 as potential targets for CRC chemoprevention or interception. Our findings suggest a promising avenue for developing drugs that may effectively intervene in the progression of colorectal cancer, offering hope for improved preventive strategies in the future.</span></p>

Novel sulindac derivatives for colorectal cancer chemoprevention that target cGMP phosphodiesterases to suppress Wnt/β-catenin transcriptional activity

<p class="MsoNormal" style="margin-top: 6pt; line-height: 13pt; text-align: justify;"><span lang="EN-US" style="font-size: 10pt; font-family: arial, helvetica, sans-serif;">Approximately 28 million individuals in the United States face the risk of developing precancerous colonic adenomas (polyps) and potentially progressing to colorectal cancer (CRC). While a promising strategy for CRC prevention involves pharmacological intervention, such as cancer chemoprevention or interception, currently, there are no FDA-approved drugs capable of preventing the formation or progression of adenomas to adenocarcinoma. Numerous clinical, epidemiological, and preclinical studies have offered compelling evidence supporting the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) in CRC chemoprevention. However, the prolonged use of NSAIDs is not FDA-approved due to potential life-threatening toxicities resulting from cyclooxygenase (COX) inhibition and the depletion of physiological prostaglandins. Despite indications that the COX inhibitory activity of NSAIDs may not be essential for their antineoplastic effects, the absence of a well-defined target impeded the development of derivatives that do not inhibit COX. Earlier research suggests that the inhibition of cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) may be responsible, at least in part, for the antineoplastic activity of the NSAID sulindac. This could potentially offer a novel target for CRC chemoprevention. To identify the cGMP PDE isozyme(s) contributing to the antineoplastic activity of sulindac, we synthesized a chemically diverse library of over 1500 compounds, all sharing the indene scaffold of sulindac. Subsequently, we screened these compounds for their impact on cancer cell growth and PDE inhibitory activity. From this screening, a series of lead compounds emerged. These compounds lacked COX-1 and COX-2 inhibitory activity, surpassing sulindac in potency to inhibit CRC cell growth. Importantly, they demonstrated greater selectivity by not affecting normal cell growth. Through chemical optimization, we identified several development candidates that selectively inhibit PDE5 and/or PDE10. These compounds activate cGMP/PKG signaling, suppressing Wnt/β-catenin transcription. This action counters the growth advantages resulting from APC or CTNNB1 mutations, which are responsible for most human CRCs. This review delves into the scientific literature supporting PDE5 and/or PDE10 as potential targets for CRC chemoprevention or interception. Our findings suggest a promising avenue for developing drugs that may effectively intervene in the progression of colorectal cancer, offering hope for improved preventive strategies in the future.</span></p>

The Promise of Piperine in Cancer Chemoprevention.

Cancer, characterized by the unregulated growth and dissemination of malignantly transformed cells, presents a significant global health challenge. The multistage process of cancer development involves intricate biochemical and genetic alterations within target cells. Cancer chemoprevention has emerged as a vital strategy to address this complex issue to mitigate cancer's impact on healthcare systems. This approach leverages pharmacologically active agents to block, suppress, prevent, or reverse invasive cancer development. Among these agents, piperine, an active alkaloid with a wide range of therapeutic properties, including antioxidant, anti-inflammatory, and immunomodulatory effects, has garnered attention for its potential in cancer prevention and treatment. This comprehensive review explores piperine's multifaceted role in inhibiting the molecular events and signaling pathways associated with various stages of cancer development, shedding light on its promising prospects as a versatile tool in cancer chemoprevention. Furthermore, the review will also delve into how piperine enhances the effectiveness of conventional treatments such as UV-phototherapy and TRAIL-based therapy, potentially synergizing with existing therapeutic modalities to provide more robust cancer management strategies. Finally, a crucial perspective of the long-term safety and potential side effects of piperine-based therapies and the need for clinical trials is also discussed.

Life cycle assessment of chemical synthesis of genistein and its glucosyl derivatives to be employed in the modulation of angiogenesis of hepatocellular cancer

This work is focused on the application of Life Cycle Assessment (LCA) methodology for the quantification of the potential environmental impacts associated to the obtainment of three glucosyl derivatives of genistein. Genistein is known to possess the ability in vitro to contribute to control signaling of some molecules like Angiopoietin-2 that has a key role in angiogenesis and fibrosis from which Hepatocellular cancer can arise. Therefore, a fine tuning of genistein uptake and bioavailability (e.g., through glycosylation) may provide innovative anti-angiogenic therapies with benefits for cancer chemoprevention and treatment.The production of pharmaceutical quality genistein, from which the derivatives are obtained, was modelled considering a recently optimized published procedure. The preparation of 7-O-(β-D-glucosyl)genistein (or genistin) was experimentally conducted by exploiting a two-step synthetic protocol. During the work-up procedure, two further derivatives were isolated.In order to also comprise the potential human health benefits of the synthesized compounds, this work also proposes for the first time a potential damage assessment factor for genistein and its derivatives.