Cancer Chemoprevention Research Articles

Should I Take Aspirin? (SITA): randomised controlled trial of a decision aid for cancer chemoprevention.

Australian guidelines recommend that people aged 50-70 years consider taking low-dose aspirin to reduce their risk of colorectal cancer (CRC). To determine the effect of a consultation with a researcher before an appointment in general practice using a decision aid presenting the benefits and harms of taking low-dose aspirin compared with a general CRC prevention brochure on patients' informed decision making and low-dose aspirin use. Individually randomised controlled trial in six general practices in Victoria, Australia, from October 2020 to March 2021. Participants were recruited from a consecutive sample of patients aged 50-70 years attending a GP. The intervention was a consultation using a decision aid to discuss taking aspirin to reduce CRC risk while control consultations discussed reducing CRC risk generally. Self-reported co-primary outcomes were the proportion of individuals making informed choices about taking aspirin at 1 month and on low-dose aspirin uptake at 6 months, respectively. The intervention effect was estimated using a generalised linear model and reported with Bonferroni-adjusted 95% confidence intervals (CIs) and P-values. A total of 261 participants (86% of eligible patients) were randomised into trial arms (n = 129 intervention; n = 132 control). Of these participants, 17.7% (n = 20/113) in the intervention group and 7.6% (n = 9/118) in the control group reported making an informed choice about taking aspirin at 1 month, an estimated 9.1% (95% CI = 0.29 to 18.5) between-arm difference in proportions (odds ratio [OR] 2.47, 97.5% CI = 0.94 to 6.52, P = 0.074). The proportions of individuals who reported taking aspirin at 6 months were 10.2% (n = 12/118) of the intervention group versus 13.8% (n = 16/116) of the control group, an estimated between-arm difference of -4.0% (95% CI = -13.5 to 5.5; OR 0.68 [97.5% CI = 0.27 to 1.70, P = 0.692]). The decision aid improved informed decision making but this did not translate into long-term regular use of aspirin to reduce CRC risk. In future research, decision aids should be delivered alongside various implementation strategies.

Abstract 2985: RXR agonist, 9cUAB30 impacts epigenetic regulations to achieve chemoprevention of UVB-induced Skin cancer by altering global miRNA profiling

Abstract Basal cell carcinoma (BCCs) and Squamous cell carcinoma (SCCs) are the most common skin neoplasms in the Caucasian population. UVB is considered as the most important etiologic factor for these cancers. The molecular mechanism regulating pathogenesis of these neoplasms is not well defined. Similar to humans Ptch+/−/SKH-1 mice develop both BCCs and SCCs, following chronic UVB-irradiation. We used TaqMan-based Open Array platform containing 796 miRNAs (miRs) to profile miRs associated with BCCs and SCCs. Pathway enrichment analysis was performed using miRPathDB databases at https://mpd.bioinf.uni-sb.de/. 81 miRNAs were differentially expressed in BCCs, of which 54 miRs had cumulative frequency of greater than 1 (FC>1) and 78 miRs were differentially expressed in SCCs, out of which 20 miRs had FC>1. miR-721 was highly induced (123.75 fold, P<0.0430) in BCCs followed by miR-2182, miR-21, miR-451, miR-124a, and miR-685 while downmodulated miRs includes miR-1, miR-133a, miR-133b, and miR-196b. Likewise, miR-21 had maximum fold induction (45.94, P<0.007) in SCCs followed by miR-2182, miR-685, miR-1938, miR-2138, and miR-451 while miR-196b, miR196c, and miR-1 were downmodulated. Kegg pathways analysis revealed that altered miRs belong to Hepatitis B, HIF-1, FoxO, chemokine, adipocytokine, NFκB, cholinergic and TLR signaling pathways. WikiPathway database showed alterations in miRs associated with neovascularization process, Notch Signaling, Pregnane X receptor, α6β4, and BDNF-TrkB signaling. To further investigate the importance of pathways associated with tumor progression, we profiled miRs in residual BCCs and SCCs procured from UAB30 treatment groups. The chemopreventive agent UAB30 is an RXR agonist. In BCCs, UAB30 treatment significantly downmodulated UVB-upregulated miRs. These miRs includes miR-210, miR-546, miR-324-3p, miR-706 and miR-1898. However, UAB30 treatment significantly upregulates miR-380-5p which was downmodulated by UVB-alone. These miRs were involved in immune regulation, Fanconi anemia pathways, FoxO signaling, prostate cancer and p53 signaling. In SCCs, UAB30 treatment significantly reversed the expression of various miRs which were downmodulated by UVB. These miRs were miR-24, miR-26a, miR-30c, miR-328, miR-30b, miR-495 and miR-2100. The expression of miR-21a-3p was downmodulated by UAB30 in SCCs of UVB-exposed group relative to SCCs of untreated but UVB-exposed group. These miRs belong to pathways involved in cell cycle progression, p53 signaling, viral carcinogenesis, Hepatitis B, Melanoma, Prostate cancer, FoxO and PI3K-AKT signaling. In summary, this profiling of miRs in UVB-induced BCC and SCC represents the underlying epigenetic mechanisms that regulate various signaling pathways in these cancers. Our data also show the critical role of miRs responsive to UAB30 treatment in cancer chemoprevention. Citation Format: Mahendra P. Kashyap, Rajesh Sinha, Craig A. Elmets, Venkatram R. Atigadda, Mohammad Athar. RXR agonist, 9cUAB30 impacts epigenetic regulations to achieve chemoprevention of UVB-induced Skin cancer by altering global miRNA profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2985.

Abstract 7305: Chemoprevention of colorectal cancer: Role of trace minerals in conjunction with calcium

Abstract Background: Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. CRC usually develops from adenomas (CRC precursors) after a long latency period. Prevention is crucial in reducing CRC incidence and progression to cancer. Among several prevention options, calcium has been a widely considered chemo-preventative agent. Aims: Calcium plays a vital role in the regulation of epithelial cell differentiation, which is essential for epithelial growth control. Epidemiological studies have demonstrated that adequate calcium intake is crucial for protection against colonic polyp formation and colorectal cancer. However, recent interventional trials with calcium have had only modest and mixed results, and the question is how to improve efficacy. One potential strategy is to use calcium in combination with additional minerals and trace elements. Results: Our preclinical studies employing monolayer cultures with CRC cell lines and colon organoids cultures from colon polyps have shown that a calcium-rich mineral combination derived from fossilized red algae (Aquamin) is more effective than calcium alone in inducing differentiation, suppressing growth and upregulation of calcium-sensing receptor. When colonic adenomas in culture were subjected to differential proteomic analysis, Aquamin upregulated several proteins involved in proliferation suppression, DNA mismatch repair and inducing differentiation, and apoptosis. Two long-term mouse studies have demonstrated that Aquamin is more effective in suppressing polyp & CRC incidence compared to calcium alone. Based on these findings, we conducted a 90-day FDA-approved trial (a pilot study with ten subjects per arm) comparing the two interventions in human subjects at risk for CRC. Results showed that Aquamin treatment reduced proliferation and increased cell differentiation observed by immunohistochemistry. Proteomic analysis also revealed that the minerals upregulated several proteins related to growth suppression, inducing differentiation and those contributing to cell-cell and cell-matrix adhesion functions and downregulated proteins involved in proliferation and nucleic acid metabolism. Conclusion: These results provide convincing evidence that a multi-mineral combination derived from red algae can provide benefits in preventing CRC that are not seen with calcium alone. Further studies, such as a polyp-prevention trial in human subjects, are warranted to advance these CRC prevention efforts. Citation Format: Isabelle Harber, Shannon McClintock, James Varani, Muhammad N. Aslam. Chemoprevention of colorectal cancer: Role of trace minerals in conjunction with calcium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7305.

Dysfunction of Nrf2-regulated cellular defence system and JNK activation induced by high dose of fly Ash particles are associated with pulmonary injury in mouse lungs

The mechanisms of the exposure to fine particulate matter (PM) as a risk factor for pulmonary injury are not fully understood. The transcription factor, NF-E2-related factor 2 (Nrf2), plays a key role in protection lung against PM insult and cancer chemoprevention. In this study, F3-S fly ash particles from a municipal waste incinerator were evaluated as a PM model. We found that F3-S triggered hierarchical oxidative stress responses involving the prolonged activation of the cytoprotective Nrf2 transcriptional program via Keap1 Cys151 modification, and c-Jun NH2-terminal kinase (JNK) phosphorylation at higher doses. In mouse lungs exposed to fly ash particles at a low dose (10–20 mg/kg), Nrf2 signalling was upregulated, while in those exposed to a high fly ash particle dose (40 mg/kg), there was significant activation of JNK, and this correlated with Nrf2 phosphorylation and the downregulation of antioxidant response element (ARE)-driven genes. The JNK inhibitor, SP600125, reversed Nrf2 phosphorylation, and downregulation of detoxifying enzymes. Silencing JNK expression in mouse lungs using adenoviral shRNA inhibited JNK activation and Nrf2 phosphorylation, promoted ARE-driven gene expression, and reduced pulmonary injury. Furthermore, we found that the 452–515 amino acid region within the Neh1 domain of Nrf2 was required for its interaction with P-JNK. We demonstrated that Nrf2 was an important P-JNK target in fly ash-induced pulmonary toxicity. JNK phosphorylated Nrf2, leading to a dysfunction of the Nrf2-mediated defence system.

Betanin Attenuates Epigenetic Mechanisms and UV-Induced DNA Fragmentation in HaCaT Cells: Implications for Skin Cancer Chemoprevention.

Dermal photoaging refers to the skin's response to prolonged and excessive ultraviolet (UV) exposure, resulting in inflammation, changes to the tissue, redness, swelling, and discomfort. Betanin is the primary betacyanin in red beetroot (Beta vulgaris) and has excellent antioxidant properties. Yet, the specific molecular mechanisms of betanin in HaCaT cells have not been fully clarified. The objective of this study was to investigate the activity of betanin and the underlying mechanisms in HaCaT cells; furthermore, in this study, we explored the protective effect of various concentrations of betanin against UVB irradiation on HaCaT cells. Additionally, we assessed its influence on the transcription of various epigenetic effectors, including members of the DNA methyltransferase (DNMT) and histone deacetylase (HDAC) families. Our findings demonstrate a notable downregulation of genes in HaCaT cells, exhibiting diverse patterns upon betanin intake. We considered the involvement of DNMT and HDAC genes in distinct stages of carcinogenesis and the limited exploration of the effects of daily exposure dosages. Our results indicate that betanin may protect the skin from damage caused by UV exposure. Further investigation is essential to explore these potential associations.

STUDY OF CHEMOPREVENTIVE ROLE OF PADDY HUSK ON CERVICAL ADENOCARCINOMA HUMAN CELL LINE (HELA CELLS)

Objective: Cervical cancer is the fourth most prevalent cancer type and the fourth primary cause of cancer-related death among women worldwide. The deficiencies of current treatments, including severe side effects and the inability to prevent progression to the metastatic stage, necessitate the investigation of alternative agents. Methods: The chemopreventive approach employing natural products such as Paddy Husk is acquiring considerable traction in the scientific community. This study examined the chemopreventive effects of Paddy Husk on HeLa cervical cancer cells. Using the TBEA method, the IC50 of the husk was determined. To evaluate the antiproliferative activity with prolonged treatment exposure, HeLa cells treated with the IC50 value were incubated for 8 days. Results: The results demonstrated that Paddy Husk extract effectively inhibited the proliferation of HeLa cells throughout the duration of the treatment. Examination under the microscope revealed that Paddy Husk extract induces apoptotic characteristics, including cell contraction, membrane rounding, membrane blebbing, the formation of apoptotic bodies, and vacuolation. A mouse skin fibroblast cell line (L929) was used to assess the in vitro safety of paddy refuse extracts at various concentrations, revealing no toxic effects on normal L929 cells. Conclusion: These findings are essential for advancing our knowledge and recognizing the potential function of Paddy Husk compounds in cervical cancer chemoprevention.

The mechanism and experimental verification of Ixeris sonchifolia promoting apoptosis of hepatocellular carcinoma based on network pharmacology: Ixeris sonchifolia Induces Hepatocellular Carcinoma Apoptosis via the PI3K/AKT Pathway

Ethnopharmacological relevanceIxeris sonchifolia alias Kudiezi, it was named Ixeris sonchifolia (Bunge) Hance, a synonym for Crepidiastrum sonchifolium (Bunge) Pak & Kawano in the https://www.iplant.cn/. And it was first published in J. Linn. Soc., Bot. 13: 108 (1873), which was named Ixeris sonchifolia (Maxim.) Hance in the MPNS (http://mpns.kew.org). As a widely distributed medicinal and edible wild plant, it possesses unique bitter-cold characteristics and constituents with various pharmacological activities. Its main antitumor substances, same as artemisinin and paclitaxel, are classified as terpenoids and have become research foci in recent years. However, its specific biological activity and role in antitumor treatment remain largely unclear. Aim of the studyThis study aimed to elucidate the molecular targets and potential mechanisms of hepatocellular carcinoma apoptosis induced by Ixeris sonchifolia. Materials and methodsWe used network pharmacology methods to analyze and screen the active ingredients and possible underlying mechanisms of Ixeris sonchifolia in treating liver cancer and employed integrative time- and dose-dependent toxicity, transcriptomics, and molecular biology approaches to comprehensively verify the function of Ixeris sonchifolia extract (IsE) in human hepatoblastoma cell (HepG2) apoptosis and its potential mechanism. ResultsA total of 169 common targets were screened by network pharmacology, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that IsE inhibited HepG2 cell activity in a time- and dose-dependent manner. Western blot analysis confirmed that IsE promoted HepG2 cell apoptosis by inhibiting the PI3K/AKT signaling pathway and that the PI3K/AKT inhibitor LY294002 also substantially enhanced IsE-induced apoptosis. The PI3K/AKT signaling pathway exhibited significant differences compared to that in the control group. ConclusionCombining network pharmacology with experimental verification, IsE inhibited mitochondrial function and the PI3K/AKT pathway while inducing hepatoma cell apoptosis. IsE may have promising potential for liver cancer treatment and chemoprevention.

Abstract A021: Pilot study of daily exemestane in patients with Endometrial Intraepithelial Neoplasia (EIN) or grade 1 endometrial cancer

Abstract Introduction: The purpose of this study is to evaluate exemestane, an aromatase inhibitor, as a potential agent for the chemoprevention of endometrial cancer. Experimental procedures: This is a multi-center, phase IIA, single arm ‘window of opportunity’ pilot study of 25 mg per day of exemestane for 21-42 days in postmenopausal patients undergoing hysterectomy for endometrial intraepithelial neoplasia (EIN) or low-grade endometrial cancer. The primary objective is to determine if there is a decrease in proliferation index, measured by percent Ki-67 expression in endometrial tissue, from pre-treatment to post-exposure. Results of Ki-67 are compared with a historic control cohort of tumors from patients matched by preoperative histologic diagnosis, age, BMI category. Specimens from the historic control cohort included a preoperative endometrial biopsy as well as a surgical specimen, separated in time by less than 42 days. Secondary outcomes include comparison of Ki67 to historic controls, circulating serum estradiol and progesterone levels, pathologic response, tissue biomarkers, safety and adverse effects. Summary of Data: Forty patients accrued to the study between January of 2018 and March of 2021. The mean age was 63 (range 52-75). Thirty-nine patients (97.5%) self identifiedself-identified as white; 1 patient (2.5%) identified as Asian. The mean BMI was 40.3 (SD 9.75, range 22.8-60.5). Preoperative diagnoses included EIN, grade 1 endometrial adenocarcinoma, and grade 2 endometrial adenocarcinoma in 11 (27.5%), 26 (65%), and 3 (7.5%) patients respectively. Thirty-nine patients (97.5%) were compliant with exemestane dosing. All patients completed the study and no patients discontinued or interrupted therapy due to treatment related adverse events. Thirty-eight patients had evaluable specimens for both pre and post-treatment Ki-67 analysis. Median Ki-67 score decreased from 40.7% [IQR (33.9%, 50.3] at baseline to 18.1% [IQR (8.8%, 31.8%)]. This represents a median absolute change from baseline of -20.4% [IQR (-29.9, -6.7), p<0.001]. In total, percentage of Ki-67 in tumor cells declined in 31 patients and increased in 7 patients. In the historic control cohort, patients also had a decrease in Ki-67 score with a median absolute change from baseline of -6.7% [IQR (-12.7%, -1.3%), p<0.001]. However, the decrease in Ki-67 was greater in the study patients than the matched historic controls, with a median difference between the groups of -13.4% [IQR= (-23.3%, 6.9%), p=0.0095]. Serum estradiol levels did not change significantly between baseline and post-treatment (p=0.16). There was a small but significant increase from baseline to post-treatment in serum progesterone (0.14 ng/mL vs 0.37 ng/mL, p<0.001). Conclusion: In this pilot window of opportunity study, exemestane demonstrates anti-proliferative effects in endometrial intraepithelial neoplasia and low-grade endometrial cancer. This agent warrants further evaluation for the chemoprevention of endometrial cancer. Citation Format: Britt K. Erickson, Lisa Barrioullet, Rebecca C. Arend, Dina El-Rayes, Mahmoud Khalifa, Amy Skubitz, Kristin Boylan, Andrew Nelson, Bharat Thyagarajan, Thomas Havighurst, Richard Chappell, Eileen Dimond, Katina Deshong, Goli Samimi, Eva Szabo, Howard Bailey. Pilot study of daily exemestane in patients with Endometrial Intraepithelial Neoplasia (EIN) or grade 1 endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A021.

Preparation and characterization of aspirin–fucoidan complex and its admirable antitumor activity on human non-small cell lung cancer cells

The purpose of this work is to prepare a novel acetylated derivative of Undaria pinnatifida fucoidan (UPFUC) with admirable antitumor activity. Fucoidan was first acetylated by acetylsalicylic acid (aspirin, ASA) to form the ASA-UPFUC complex. The antitumor efficacy results stated that ASA-UPFUC inhibited the proliferation of human non-small cell lung cancer A549 cells in a dose-dependent manner, with an IC50 value of 49.09 μg/mL, 50.20 % lower than that of UPFUC. Importantly, the acetylation process had no adverse effects on the backbone structure of UPFUC. Simultaneously, ASA-UPFUC demonstrated a larger charge density than UPFUC, leading to enhanced solubility, improved surface charge effects, and a greater potential for exerting biological activity. Consequently, ASA-UPFUC increased the formation of alkyl and hydrogen bonds with tumor necrosis factor related apoptosis-inducing ligand receptors DR4 and DR5, thereby effectively stimulating the generation of cellular reactive oxygen species, diminishing mitochondrial membrane potential, suppressing nuclear factor κB (NFκB) p65 phosphorylation, enhancing the contents of Bax and cleaved caspase 3, and reducing the level of Bcl-2. The collective effects ultimately triggered the mitochondrial apoptotic pathway, leading to apoptosis in A549 cells. The findings support the potential utilization of ASA-UPFUC as a novel dietary additive for human lung cancer chemoprevention.

Morusin-Cu(II)-indocyanine green nanoassembly ignites mitochondrial dysfunction for chemo-photothermal tumor therapy

Nanoscale drug delivery systems derived from natural bioactive materials accelerate the innovation and evolution of cancer treatment modalities. Morusin (Mor) is a prenylated flavonoid compound with high cancer chemoprevention activity, however, the poor water solubility, low active pharmaceutical ingredient (API) loading content, and instability compromise its bioavailability and therapeutic effectiveness. Herein, a full-API carrier-free nanoparticle is developed based on the self-assembly of indocyanine green (ICG), copper ions (Cu2+) and Mor, termed as IMCNs, via coordination-driven and π-π stacking for synergistic tumor therapy. The IMCNs exhibits a desirable loading content of Mor (58.7 %) and pH/glutathione (GSH)-responsive motif. Moreover, the photothermal stability and photo-heat conversion efficiency (42.8 %) of IMCNs are improved after coordination with Cu2+ and help to achieve photothermal therapy. Afterward, the released Cu2+ depletes intracellular overexpressed GSH and mediates Fenton-like reactions, and further synergizes with ICG at high temperatures to expand oxidative damage. Furthermore, the released Mor elicits cytoplasmic vacuolation, expedites mitochondrial dysfunction, and exerts chemo-photothermal therapy after being combined with ICG to suppress the migration of residual live tumor cells. In vivo experiments demonstrate that IMCNs under laser irradiation could excellently inhibit tumor growth (89.6 %) through the multi-modal therapeutic performance of self-enhanced chemotherapy/coordinated-drugs/ photothermal therapy (PTT), presenting a great potential for cancer therapy.

Natural Compounds in Non-Melanoma Skin Cancer: Prevention and Treatment.

The elevated occurrence of non-melanoma skin cancer (NMSC) and the adverse effects associated with available treatments adversely impact the quality of life in multiple dimensions. In connection with this, there is a necessity for alternative approaches characterized by increased tolerance and lower side effects. Natural compounds could be employed due to their safety profile and effectiveness for inflammatory and neoplastic skin diseases. These anti-cancer drugs are often derived from natural sources such as marine, zoonotic, and botanical origins. Natural compounds should exhibit anti-carcinogenic actions through various pathways, influencing apoptosis potentiation, cell proliferation inhibition, and metastasis suppression. This review provides an overview of natural compounds used in cancer chemotherapies, chemoprevention, and promotion of skin regeneration, including polyphenolic compounds, flavonoids, vitamins, alkaloids, terpenoids, isothiocyanates, cannabinoids, carotenoids, and ceramides.

Toward Cancer Chemoprevention: Mathematical Modeling of Chemically Induced Carcinogenesis and Chemoprevention

Cancer, which is currently rated as the second-leading cause of mortality across the globe, is one of the most hazardous disease groups that has plagued humanity for centuries. The experiments presented here span over two decades and were conducted on a specific species of mice, aiming to neutralize a highly carcinogenic agent by altering its chemical structure when combined with certain compounds. A plethora of growth models, each of which makes use of distinctive qualities, are utilized in the investigation and explanation of the phenomena of chemically induced oncogenesis and prevention. The analysis ultimately results in the formalization of the process of locating the growth model that provides the best descriptive power based on predefined criteria. This is accomplished through a methodological workflow that adopts a computational pipeline based on the Levenberg–Marquardt algorithm with pioneering and conventional metrics as well as a ruleset. The developed process simplifies the investigated phenomena as the parameter space of growth models is reduced. The predictability is proven strong in the near future (i.e., a 0.61% difference between the predicted and actual values). The parameters differentiate between active compounds (i.e., classification results reach up to 96% in sensitivity and other performance metrics). The distribution of parameter contribution complements the findings that the logistic growth model is the most appropriate (i.e., 44.47%). In addition, the dosage of chemicals is increased by a factor of two for the next round of trials, which exposes parallel behavior between the two dosages. As a consequence, the study reveals important information on chemoprevention and the cycles of cancer proliferation. If developed further, it might lead to the development of nutritional supplements that completely inhibit the expansion of cancerous tumors. The methodology provided can be used to describe other phenomena that progress over time and it has the power to estimate future results.

The Use of Isoflavones as Lung Cancer Chemoprevention Agents and their Implications in Treatment through Radio Sensitization.

Epidemiological trends in cancer research show that lung cancer can affect up to 1 in 15 men and 1 in 17 women. With incidence rates as high as these and significant associated mortality and morbidity, it is no wonder that lung cancer is one of the main areas of research focused on cancer. Advances in targeted treatments and specialized irradiation protocols have allowed the treatment of more advanced cases. However, as the patient numbers grow, so does the need for cancer-preventive strategies. The present narrative review focuses on soy isoflavones' role in the chemoprevention of lung cancer and their possible role in therapeutic adjuncts. Laboratory studies on lung cancer cell lines have shown that isoflavones can induce apoptosis, tamper with the expression of proliferative molecular pathways, and even reduce tumor angiogenesis. Additionally, population-level studies have emerged that correlate the consumption of isoflavonoids with reduced risk for the development of lung cancer. Interestingly enough, the literature also contains small-scale studies with evidence of isoflavones being effective chemotherapeutic adjuncts that are currently understudied. Our literature review underlines such findings and provides a call for the enhancement of research regarding naturally occurring dietary products with possible anticarcinogenic effects.

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.

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.