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Background: Cancer and diabetes mellitus are quite common diseases found together worldwide. A considerable amount of evidence is available for the rapid development and presentation of various types of cancer in the type 2 diabetes mellitus (DM2) population as compared with the population without diabetes. The objective of the study is to formulate and evaluate 5-fluorouracil (5-FU) and metformin (MET) nanoparticles (NPs) and to establish the characteristic features of the biodegradable NPs. 5-FU and MET NPs with chitosan as a biodegradable polymer were formulated by the ionotropic cross-linking method. 0.25 gm of MET and 0.25 gm of 5-FU were dissolved in 100 ml of distilled water, and stock solution was prepared. 5 ml of stock solution was slowly mixed into the chitosan solution to obtain the mixture of drugs and chitosan. The tripolyphosphate reserve liquid was dripped slowly into the chitosan solution with constant stirring until the opaline appearance was noticed in the mixture, then filtered, and dried. The NPs were evaluated for their physical properties and drug release kinetics. Cell proliferation assay was done using human colorectal carcinoma cell line (HCT 116). Results: The formulation composed of 1.5 w/v of chitosan, 0.25 w/v of MET, and 5-FU had an average particle diameter of 198.7 nm. The polydispersity index was 0.757. Thermal and infrared spectroscopy results indicated the drugs and polymers selected for the formulation were unique without any identifiable interaction. The NPs were spherical in appearance, with numerous pours on the surface, which was evident when microscopically examined. Uniformity in drug release was observed, and the formulation demonstrated excellent release kinetics. HTC 116 cell line confirmed that the maximum percentage of cell death and minimum viability of cells were observed while using the combination of MET and 5-FU-NPs as compared to the pure MET or 5-FU alone. Conclusion: MET and 5-FU-loaded chitosan NPs were found to have excellent physiochemical properties, particle size, and drug release from the polymer in a controlled manner. Half-maximal inhibitory concentration value (IC50) of MET and 5-FU-NPs was found to be significantly less as compared to MET and 5-FU alone or the combination. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the top 10 most common cancers worldwide and caused approximately 10 million deaths in 2022. CRC mortality has increased by 10% since 2020 and 52.000 deaths will occur in 2024, highlighting the limitations of current treatments due to ineffectiveness, toxicity, or non-adherence. The widely used chemotherapeutic agent, 5-fluorouracil (5-FU), is associated with several adverse effects, including renal, cardiac, and hepatic toxicity; mucositis; and resistance. Taurine (TAU), an essential β-amino acid with potent antioxidant, antimutagenic, and anti-inflammatory properties, has demonstrated protective effects against tissue toxicity from chemotherapeutic agents like doxorubicin and cisplatin. Taurine deficiency is linked to aging and cancers such as breast and colon cancer. This study hypothesized that TAU may mitigate the adverse effects of 5-fluorouracil (5-FU). Carcinogenesis was chemically induced in rats using 1,2-dimethylhydrazine (DMH). Following five months of cancer progression, taurine (100 mg/kg) was administered orally for 8 days, and colon tissues were analyzed. The results showed 80% of adenocarcinoma (AC) in DMH-induced control animals. Notably, the efficacy of 5-FU showed 70% AC and TAU 50% while, in the 5-FU + TAU group, no adenocarcinoma was observed. No differences were observed in the inflammatory infiltrate or the expression of genes such as K-ras, p53, and Ki-67 among the cancer-induced groups whereas APC/β-catenin expression was increased in the 5FU + TAU-treated group. The mitotic index and dysplasia were increased in the induced 5-FU group and when associated with TAU, the levels returned to normal. These data suggest that 5-FU exhibits a synergic anticancer effect when combined with taurine. [ABSTRACT FROM AUTHOR]

Colon cancer is the third most common cancer worldwide, with high mortality. Adverse side effects and chemoresistance of the first-line chemotherapy 5-fluorouracil (5-FU) have promoted the widespread use of combination therapies. Thymoquinone (TQ) is a natural compound with potent antioxidant activity. Loading antioxidants into nano delivery systems has been a major advance in enhancing their bioavailability to improve clinical application. Hence, this study aimed to prepare the optimal TQ-loaded calcium carbonate nanoparticles (TQ-CaCO3 NPs) and investigate their therapeutic potential and underlying molecular mechanisms of TQ-CaCO3 NPs in combination with 5-FU against colon cancer. Firstly, we developed purely aragonite CaCO3 NPs with a facile mechanical ball-milling method. The pH-sensitive and biocompatible TQ-CaCO3 NPs with sustained release properties were prepared using the optimal synthesized method (a high-speed homogenizer). The in vitro study revealed that the combination of TQ-CaCO3 NPs (15 μM) and 5-FU (7.5 μM) inhibited CT26 cell proliferation and migration, induced cell apoptosis and cell cycle arrest in the G0/G1 phase, and suppressed the CT26 spheroid growth, exhibiting a synergistic effect. Finally, network pharmacology and molecular docking results indicated the potential targets and crucial signaling pathways of TQ-CaCO3 NPs in combination with 5-FU against colon cancer. Therefore, TQ-CaCO3 NPs combined with 5-FU could enhance the anti-colon cancer effects of 5-FU with broader therapeutic targets, warranting further application for colon cancer treatment. [ABSTRACT FROM AUTHOR]

As a chemotherapy drug, 5‐fluorouracil (5‐FU) has been used for colon cancer for decades. Excessive levels of 5‐FU in the human body can lead to notable adverse effects, including severe diarrhea, infection, mouth sores, skin peeling, skin inflammation, and ulcers, which are important and relatively common digestive side effects. In addition, 5‐FU is an analog of uracil and also has similarities to pyrimidines. Therefore, it is not easy to separate them. This research presented a sensor capable of detecting drugs in minimal amounts. An alginate‐derived carbon dot (CD) was synthesized by unique optical properties that obey an on–off fluorescence mechanism for 5‐FU sensing. Introducing copper (Cu(I)) to CDs results in fluorescence quenching through electron transfer. However, when 5‐FU is added to the system as an oxidizing agent, a redox reaction occurs on the surface of the CDs, which leads to the restoration of fluorescence as Cu(I) is altered to Cu(II). Experimental results showed a strong linear correlation (R2 = 0.99) in the concentration range of 1.00–45.00 nM, with the following linear regression, and revealed the relative standard deviation (RSD%) and detection limit of 2.57%, and 1.00 nM, respectively. These results validated the excellent detection capability of the proposed method even at low concentrations of 5‐FU and in the presence of other drugs and interfering substances. Also, the recovery of 5‐FU (varies from 100.46% to 113.7%, with RSD equal to 1.89–3.63) in serum samples indicates the absence of matrix interference in the determination of 5‐FU. In summary, this novel approach to developing a cost‐effective and sensitive sensor holds great potential for future applications in healthcare and related fields. [ABSTRACT FROM AUTHOR]

Background: 5-Fluorouracil (5-FU) is a chemotherapy drug commonly used in the treatment of colon cancer. There is a significant drive to mitigate the limitations of 5-fluorouracil while maintaining its therapeutic potency by exploring the potential of using natural products such as curcumin in conjunction with 5-FU. Thus, the present study investigates the in vitro pharmacodynamic interaction between 5-FU and curcumin using the Chou-Talalay method in HT29 cell lines. Materials and Methods: Initially, the estimation of half-maximal concentration of the medications against HCT116 and HT29 cell lines was performed by 3-4,5-dimethylthiazol-2-yl-2,5 diphenyl tetrazolium bromide assay. Later, the combination effect was studied in HT29 cell lines by constant ratio experiment design. Results and Discussion: The research findings revealed that the 5-FU and curcumin exhibit dose-dependent anti-proliferative activity in HCT116 and HT29 cells. Moreover, it was observed that HT29 cell lines are less sensitive to 5-FU than HCT116 cell lines, rather than curcumin was found to inhibit cell proliferation in both cell lines with no significant statistical difference (p<0.05). The Combination Index (CI) values of less than 1 for all the combined experimental ratios indicated the synergistic effect of the two compounds. The generated Dose Reduction Index (DRI) values for the combination imply for the favourable dose reduction in the treatment of colorectal cancer. Conclusion: Significantly, the study indicates that 40:1 ratio of 5-FU to curcumin might represent an ideal proportion for co-administration using an appropriate delivery system. [ABSTRACT FROM AUTHOR]

Background: In vitro drug screening that is more translatable to the in vivo tumor environment can reduce both time and cost of cancer drug development. Here we address some of the shortcomings in screening and show how treatment with 5‐fluorouracil (5‐FU) in 2D and 3D culture models of colorectal cancer (CRC) and pancreatic ductal adenocarcinomas (PDAC) give different responses regarding growth inhibition. Methods: The sensitivity of the cell lines at clinically relevant 5‐FU concentrations was monitored over 4 days of treatment in both 2D and 3D cultures for CRC (SW948 and HCT116) and PDAC (Panc‐1 and MIA‐Pa‐Ca‐2) cell lines. The 3D cultures were maintained beyond this point to enable a second treatment cycle at Day 14, following the timeline of a standard clinical 5‐FU regimen. Results: Evaluation after one cycle did not reveal significant growth inhibition in any of the CRC or PDAC 2D models. By the end of the second cycle of treatment the CRC spheroids reached 50% inhibition at clinically achievable concentrations in the 3D model, but not in the 2D model. The PDAC models were not sensitive to clinical doses even after two cycles. High content viability metrics point to even lower response in the resistant PDAC models. Conclusion: This study reveals the limitations of testing drugs in 2D cancer models and short exposure in 3D models, and the importance of using appropriate growth inhibition analysis. We found that screening with longer exposure and several cycles of treatment in 3D models suggests a more reliable way to assess drug sensitivity. [ABSTRACT FROM AUTHOR]

Background: 5-fluorouracil (5-FU) is conventionally used in chemotherapy for colon adenocarcinomas. Acquired resistance of 5-FU remains a clinical challenge in colon cancer, and efforts to develop targeted agents to reduce resistance have not yielded success. Protosappanin B (PSB), the main component of Lignum Sappan extract, is known to exhibit anti-tumor effects. However, whether and how PSB could improve 5-FU resistance in colon cancer have not yet been established. In this study, we aimed to explore the effects and underlying mechanisms of PSB in 5-FU-induced chemoresistance in colon adenocarcinoma. Methods: Forty-seven paired colon cancer tissue samples from patients who received 5-FU chemotherapy were collected as clinical samples. Two 5-FU resistant colon cancer cell lines were established for in vitro experiments. Reverse transcription-quantitative PCR (RT-qPCR) was performed to determine the mRNA and microRNA (miRNA) expression levels in colon adenocarcinoma tissues and cell lines. Cell Counting Kit-8 (CCK-8) and flow cytometry assays were performed to evaluate cell proliferation and apoptosis, respectively. Results: LINC00612 was highly expressed in colon adenocarcinoma samples and 5-FU resistant colon cancer cells. LINC00612 knockdown enhances 5-FU chemosensitivity in 5-FU resistant cells. Notably, PSB treatment attenuated LINC00612 expression in 5-FU resistant colon adenocarcinoma cells. Moreover, PSB treatment reversed the increase in LINC00612-induced 5-FU resistance. Mechanistically, LINC00612 specifically bound to miR-590-3p, which promoted 5-FU resistance in colon adenocarcinoma cells and attenuated the inhibitory effect of LINC00612 on GOLPH3 expression. Conclusion: PSB attenuates 5-FU chemoresistance in colon adenocarcinoma by regulating the LINC00612/miRNA-590-3p/GOLPH3 axis. Highlights: LINC00612 is highly expressed in 5-FU resistant colon cancer cells and LINC00612 knockdown enhances 5-FU chemosensitivity in 5-FU resistant cells. PSB reverses the elevated LINC00612-induced 5-FU resistance. PSB attenuates 5-FU chemoresistance in colon adenocarcinoma by regulating the LINC00612/miRNA-590-3p/GOLPH3 axis. [ABSTRACT FROM AUTHOR]

Colon cancer (CC) management includes surgery, radio- and chemotherapy based on treatment with 5-fluorouracil (5-FU) or its derivatives. However, its application is limited to low-grade carcinomas. Thus, much research has been conducted to introduce new techniques and drugs to the therapy. CC mostly affects older people suffering from cardiac diseases, where iron compounds are commonly used. Ferric citrate and iron (III)–EDTA complexes have proven to be effective in colon cancer in vitro. This study aimed to determine the potency and action of iron-containing compounds in colon cancer treatment by chemo- and electrochemotherapy in both nano- and microsecond protocols. The viability of the cells was assessed after standalone iron (III) citrate and iron (III)–EDTA incubation. Both compounds were also assessed with 5-FU to determine the combination index. Additionally, frataxin expression was taken as the quantitative response to the exposition of iron compounds. Each of the substances exhibited a cytotoxic effect on the LoVo cell line. Electroporation with standalone drugs revealed the potency of 5-FU and iron(III)–EDTA in CC treatment. The combination of 5-FU with iron(III)–EDTA acted synergistically, increasing the viability of the cells in the nanosecond electrochemotherapy protocol. Iron(III)–EDTA decreased the frataxin expression, thus inducing ferroptosis. Iron(III) citrate induced the progression of cancer; therefore, it should not be considered as a potential therapeutic option. The relatively low stability of iron(III) citrate leads to the delivery of citrate anions to cancer cells, which could increase the Krebs cycle rate and promote progression. [ABSTRACT FROM AUTHOR]

A growing number of studies have suggested the involvement of long non-coding RNAs as the key players in not just the initiation and progression of the tumor microenvironment, but also in chemotherapy tolerance. In the present study, generated 5-FU-resistant SW480/DR cells were analyzed via cDNA microarray for its aberrant lncRNAs and mRNAs expression in comparison with the 5-FU-susceptible SW480/DS cells. Among the 126 lncRNAs described, lncRNAs GNAS-AS1, MIR205HG, and LOC102723721 have been identified to be significantly upregulated, while lncRNs lnc-RP11-597K23.2.1-2, LOC100507639, and CCDC144NL-AS1 have been found to be significantly downregulated. In the meantime, bioinformatic analysis through gene ontology studies of aberrantly expressed mRNAs revealed "regulated exocytosis", among others, as the biological process most impacted in SW480/DR cells. To investigate, exosome purification was then carried out and its characterization were validated via transmission electron microscopy and nanoparticle tracking analysis. Interestingly, it was determined that the 5-FU-resistant SW480/DR cells secretes significantly higher concentration of extracellular vesicles, particularly, exosomes when compared to the 5-FU-susceptible SW480/DS cells. Based on the lncRNA-mRNA interaction network analysis generated, lncRNA GNAS-AS1 and MIR205HG have been identified to be potentially involved in the incidence of 5-FU resistance in SW480 colon cancer cells through promoting increased release of exosomes into the intercellular matrix. Our study hopes not only to provide insights on the list of involved candidate lncRNAs, but also to elucidate the role exosomes play in the initiation and development of 5-FU chemotherapy resistance in colon cancer cells. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the top 10 most common cancers worldwide and caused approximately 10 million deaths in 2022. CRC mortality has increased by 10% since 2020 and 52.000 deaths will occur in 2024, highlighting the limitations of current treatments due to ineffectiveness, toxicity, or non-adherence. The widely used chemotherapeutic agent, 5-fluorouracil (5-FU), is associated with several adverse effects, including renal, cardiac, and hepatic toxicity; mucositis; and resistance. Taurine (TAU), an essential β-amino acid with potent antioxidant, antimutagenic, and anti-inflammatory properties, has demonstrated protective effects against tissue toxicity from chemotherapeutic agents like doxorubicin and cisplatin. Taurine deficiency is linked to aging and cancers such as breast and colon cancer. This study hypothesized that TAU may mitigate the adverse effects of 5-fluorouracil (5-FU). Carcinogenesis was chemically induced in rats using 1,2-dimethylhydrazine (DMH). Following five months of cancer progression, taurine (100 mg/kg) was administered orally for 8 days, and colon tissues were analyzed. The results showed 80% of adenocarcinoma (AC) in DMH-induced control animals. Notably, the efficacy of 5-FU showed 70% AC and TAU 50% while, in the 5-FU + TAU group, no adenocarcinoma was observed. No differences were observed in the inflammatory infiltrate or the expression of genes such as K-ras, p53, and Ki-67 among the cancer-induced groups whereas APC/β-catenin expression was increased in the 5FU + TAU-treated group. The mitotic index and dysplasia were increased in the induced 5-FU group and when associated with TAU, the levels returned to normal. These data suggest that 5-FU exhibits a synergic anticancer effect when combined with taurine.

To fulfil the synergistic delivery and on-demand drug release of 5-fluorouracil (5-FU) and methotrexate (MTX) at tumor sites, we innovatively synthesized pH and redox responsive self-assembling nanoparticles based on ZIF-8 frameworks as the 5-FU vehicle decorated with hyaluronic acid-MTX bioconjugates linked with a redox-responsive disulfide bond. The constructed HA-SS-MTX/5-FU@ZIF-8 nanoplatform exhibited monodisperse and spherical shape with a mean hydrodynamic diameter of 161.0nm and loaded about 0.345 g of 5-FU and 0.0508 g of MTX per gram. The preliminary in vitro experiments showed that the as-prepared HA-SS-MTX/5-FU@ZIF-8 nanoparticles (NPs) displayed high inhibiting proliferation and promoting apoptosis performance towards the colon cancer cells. [ABSTRACT FROM AUTHOR]

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Colon cancer is the third most common cancer worldwide, with high mortality. Adverse side effects and chemoresistance of the first-line chemotherapy 5-fluorouracil (5-FU) have promoted the widespread use of combination therapies. Thymoquinone (TQ) is a natural compound with potent antioxidant activity. Loading antioxidants into nano delivery systems has been a major advance in enhancing their bioavailability to improve clinical application. Hence, this study aimed to prepare the optimal TQ-loaded calcium carbonate nanoparticles (TQ-CaCO3 NPs) and investigate their therapeutic potential and underlying molecular mechanisms of TQ-CaCO3 NPs in combination with 5-FU against colon cancer. Firstly, we developed purely aragonite CaCO3 NPs with a facile mechanical ball-milling method. The pH-sensitive and biocompatible TQ-CaCO3 NPs with sustained release properties were prepared using the optimal synthesized method (a high-speed homogenizer). The in vitro study revealed that the combination of TQ-CaCO3 NPs (15 μM) and 5-FU (7.5 μM) inhibited CT26 cell proliferation and migration, induced cell apoptosis and cell cycle arrest in the G0/G1 phase, and suppressed the CT26 spheroid growth, exhibiting a synergistic effect. Finally, network pharmacology and molecular docking results indicated the potential targets and crucial signaling pathways of TQ-CaCO3 NPs in combination with 5-FU against colon cancer. Therefore, TQ-CaCO3 NPs combined with 5-FU could enhance the anti-colon cancer effects of 5-FU with broader therapeutic targets, warranting further application for colon cancer treatment.

Aim: Hesperidin is an important flavonoid compound of citrus fruits. It has the potential to be evaluated as a cytotoxic agent against a variety of malignant human cancer cells, especially in colon, pancreatic, breast, and other cancer types. The practical application of combination therapies is commonly used to eliminate or reduce drug resistance. Materials and Methods: In this study, hesperidin (0.001-300µM) and 5-fluorouracil (5-FU) (1-300 µM), a cytotoxic chemotherapy drug used for treating cancer, were applied both individually and in combination (100 µM) on the HT-29 cells (human colon cancer cell line). The effects of these compounds on HT-29 cell viability were revealed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method, and the genotoxic effects on HT-29 cells were revealed using single-cell gel electrophoresis analysis. Results: The data obtained showed that the combination of 5-FU and hesperidin importantly decreased HT-29 cell viability compared to the group treated with 5-FU alone. These findings indicate that the combined application of these compounds is more effective than the individual administration of 5-FU or hesperidin alone. Conclusion: The research suggests that hesperidin might possess the ability to counter drug resistance in cancer cells, offering promising prospects when used alongside current anti-cancer medications. Nevertheless, to validate these findings, more extensive research and clinical trials are imperative. [ABSTRACT FROM AUTHOR]

Objective: To investigate the therapeutic effects and mechanisms of Feng-Liao-Chang-Wei-Kang combined with 5-fluorouracil administration in mice with colitis-associated colon cancer. Methods: To establish a colitis-associated colon cancer mouse model and observe the behavior and activity of mice after Feng-Liao-Chang-Wei-Kang and 5-fluorouracil administration; HE staining to observe the pathological changes of mouse colonic tissue; Western blot was used to detect the expression of mouse colon tissue in IL-6/STAT3 pathway-related proteins. Results: The survival rate of mice in the co-administered group was significantly increased, and the intestinal wall thickening and interstitial inflammation of mice were significantly reduced. Western blot results showed that the expression levels of P-STAT3 and IL-6 were significantly increased in the colonic tissue of mice after modeling, and the combined administration inhibited the expression of Cyclin D1, CDK4 and Bcl-2 protein in the IL-6/STAT3 pathway and upregulated the expression of Bax(P<0.05). Conclusion: Feng-Liao-Chang-Wei-Kang combined with 5-fluorouracil inhibits IL-6/STAT3 pathway to exert inhibition of colitisassociated colon cancer inhibition of colitis-associated colon cancer. [ABSTRACT FROM AUTHOR]

Colon cancer (CC) management includes surgery, radio- and chemotherapy based on treatment with 5-fluorouracil (5-FU) or its derivatives. However, its application is limited to low-grade carcinomas. Thus, much research has been conducted to introduce new techniques and drugs to the therapy. CC mostly affects older people suffering from cardiac diseases, where iron compounds are commonly used. Ferric citrate and iron (III)–EDTA complexes have proven to be effective in colon cancer in vitro. This study aimed to determine the potency and action of iron-containing compounds in colon cancer treatment by chemo- and electrochemotherapy in both nano- and microsecond protocols. The viability of the cells was assessed after standalone iron (III) citrate and iron (III)–EDTA incubation. Both compounds were also assessed with 5-FU to determine the combination index. Additionally, frataxin expression was taken as the quantitative response to the exposition of iron compounds. Each of the substances exhibited a cytotoxic effect on the LoVo cell line. Electroporation with standalone drugs revealed the potency of 5-FU and iron(III)–EDTA in CC treatment. The combination of 5-FU with iron(III)–EDTA acted synergistically, increasing the viability of the cells in the nanosecond electrochemotherapy protocol. Iron(III)–EDTA decreased the frataxin expression, thus inducing ferroptosis. Iron(III) citrate induced the progression of cancer; therefore, it should not be considered as a potential therapeutic option. The relatively low stability of iron(III) citrate leads to the delivery of citrate anions to cancer cells, which could increase the Krebs cycle rate and promote progression.

A growing number of studies have suggested the involvement of long non-coding RNAs as the key players in not just the initiation and progression of the tumor microenvironment, but also in chemotherapy tolerance. In the present study, generated 5-FU-resistant SW480/DR cells were analyzed via cDNA microarray for its aberrant lncRNAs and mRNAs expression in comparison with the 5-FU-susceptible SW480/DS cells. Among the 126 lncRNAs described, lncRNAs GNAS-AS1, MIR205HG, and LOC102723721 have been identified to be significantly upregulated, while lncRNs lnc-RP11-597K23.2.1-2, LOC100507639, and CCDC144NL-AS1 have been found to be significantly downregulated. In the meantime, bioinformatic analysis through gene ontology studies of aberrantly expressed mRNAs revealed “regulated exocytosis”, among others, as the biological process most impacted in SW480/DR cells. To investigate, exosome purification was then carried out and its characterization were validated via transmission electron microscopy and nanoparticle tracking analysis. Interestingly, it was determined that the 5-FU-resistant SW480/DR cells secretes significantly higher concentration of extracellular vesicles, particularly, exosomes when compared to the 5-FU-susceptible SW480/DS cells. Based on the lncRNA-mRNA interaction network analysis generated, lncRNA GNAS-AS1 and MIR205HG have been identified to be potentially involved in the incidence of 5-FU resistance in SW480 colon cancer cells through promoting increased release of exosomes into the intercellular matrix. Our study hopes not only to provide insights on the list of involved candidate lncRNAs, but also to elucidate the role exosomes play in the initiation and development of 5-FU chemotherapy resistance in colon cancer cells.

Due to the increase in new types of cancer cells and resistance to drugs, conventional cancer treatments are sometimes insufficient. Therefore, an alternative is to apply nanotechnology to biomedical areas, minimizing side effects and drug resistance and improving treatment efficacy. This work aims to find a promising cancer treatment in the human colorectal adenocarcinoma cell line (HT-29) to minimize the viability of cells (IC50) by using carbon nanotubes (CNTs) combined with different drugs (5-fluorouracil (5-FU) and two repurposing drugs—tacrine (TAC) and ethionamide (ETA). Several CNT samples with different functional groups (-O, -N, -S) and textural properties were prepared and characterized by elemental and thermogravimetry analysis, size distribution, and textural and temperature programmed desorption. The samples that interacted most with the drugs and contributed to improving HT-29 cell treatment were samples doped with nitrogen and sulfur groups (CNT-BM-N and CNT-H2SO4-BM) with IC50 1.98 and 2.50 µmol∙dm−3 from 5-FU and 15.32 and 15.81 µmol∙dm−3 from TAC. On the other hand, ETA had no activity, even combined with the CNTs. These results allow us to conclude that the activity was improved for both 5-FU and TAC when combined with CNTs. [ABSTRACT FROM AUTHOR]

Kolon kanseri, tüm dünyada yaygın olan ve yüksek oranda ölümcül bir kanser tipidir. Tüm kanserlerde olduğu gibi kolon kanserinin seyrinin izlenmesi kritik bir öneme sahiptir. 5-Florourasil (5-FU) kolon kanserlerinde sıklıkla kullanılan bir antikanser ilaçtır ve hücre ölümü esnasında hücrelerde bir takım biyokimyasal ve moleküler farklılıklara neden olmaktadır. Bu çalışmada HCT116 ve HT29 kolon kanseri hücreleri 5-FU kemoterapi ilacı ile inkübe edildikten sonra, 5FU’nun hücreler üzerinde oluşturduğu biyokimyasal değişikliğin tespiti için Fourier transform kızılötesi (FTIR) spektroskopisi kullanılmıştır. 5-FU'nun inhibisyon yüzdesinin 50'ye eşit olduğu konsantrasyonu (IC50), MTT yöntemi kullanılarak belirlendi. IC50 değeri saptandıktan sonra FTIR ölçümleri alındı. Buna göre, 5-FU IC50 değeri sırasıyla HCT116 hücreleri için 12,69 µg/ml, HT29 hücreleri için 10,10 µg/ml bulunmuştur. 5-FU’nun sebep olduğu hücre ölümünün göstergeleri olduğu söylenen lipit içeriğindeki artış ile nükleik asit oranı, total hücresel proteinlerin α-sarmal ve β-yaprak ikincil yapıları ve aminoasit kalıntılarının azalması, kollajen konformasyonundaki değişiklikler gibi IR biyobelirteçlerindeki değişiklikler FTIR spektroskopisi ile gösterilmiştir. Sonuç olarak hem ucuz ve hem de hızlı bir yöntem olan FTIR ile kanser hücre ölümünün incelenmesi alternatif bir yöntem olarak kullanılabilir.

The successful chemotherapeutic regime required for the clinical management of different cancers largely depends on the efficient drug delivery within the cancer cells. Exosomes have emerged as an enticing candidate for exploring their role as delivery vehicles. Exosomes are reported to be intrinsically nanosized vesicles competent for efficient delivery across the cellular membrane. In the present study, we assessed the feasibility of an autologous exosome‐based drug delivery platform for delivering 5‐Fluorouracil (5‐FU) against human colon cancer HCT116 cells. Autologous exosomes have shown probable tropism toward the tumor microenvironment, which makes them the most competitive vehicle for drug delivery. It was observed that the autologous exosomes loaded with 5‐FU showed an enhanced rate of drug release under acidic conditions. The result of the cell viability assay showed that treatment of 5‐FU‐loaded exosomes (equivalent to 5 μg 5‐FU) resulted in enhanced cytotoxic effect in HCT116 cells as compared to an equivalent amount of free 5‐FU (5 μg), which elucidated the efficient delivery of the 5‐FU by exosomes inside the cancer cells. Subsequently, 5‐FU‐loaded exosomes led to increased nuclear condensation and fragmentation along with increased ROS production. In addition, 5‐FU‐loaded exosomes caused enhanced dissipation of mitochondrial membrane potential and caspase‐3 activation, resulting in increased apoptosis induction. Our study also revealed that 5‐FU‐loaded exosomes upsurged the arrest in the cell cycle at the G0/G1 stage in HCT‐116 cells and it was found to be associated with decreased CDK4 and Cyclin D1 expression concomitantly with the upregulation of CDK inhibitor, p21Cip1 expression. Thus, the findings from the present study highlight the advantages of autologous exosomes as a natural drug carrier which could efficiently deliver chemotherapeutic drugs to cancer cells. [ABSTRACT FROM AUTHOR]

Purpose: To design pH switchable LLC (lyotropic liquid crystal) nanoparticles with the goal of exclusively delivering 5-Fluorouracil (5-FU) in the colonic region of GIT for the treatment of colon cancer. Methods: The proportions of monoolein (MO), oleic acid (OA), and pluronic F127 were chosen using the quadratic model of D-optimal mixture design for LLC nanoparticle batches. The formulations were characterized and evaluated for (i) adhesion work at porcine stomach, (ii) adhesion work at porcine large intestine, (iii) drug release up to pH 6.8, and (iv) drug release at pH 7.4. The models developed during data analysis were optimized and subjected to pharmacokinetic and in vivo scintigraphic study. Results: The design proposed three optimal formulations OLN1, OLN2, and OLN3, where OLN3 outperformed the rest in terms of 5-FU release profile as well as comparable work of adhesion at porcine stomach and large intestine. The gamma scintigraphic images and pharmacokinetic results of OLN3 with 30% MO, 62.565% OA, and 7.435% pluronic F127 indicated that the hexagonal configuration of the system prevented 5-FU absorption from the upper GIT and no substantial release of the drug occurred within 6-h period. However, there was considerable release from the system due to hexagonal structure converting to cubic structure at colonic pH. Conclusions: Upon oral administration, OLN3 preserved its integrity during its passage through stomach, successfully entered, and was evenly spread in the colon during the 12-h study period demonstrating the required properties in terms of drug targeting. [ABSTRACT FROM AUTHOR]

Probiotic strains such as Lactobacillus spp. are already known for their beneficial effect on human health and new research supports their role in colon cancer prevention and treatment. The current study reports the effect of different concentrations of Lacticaseibacillus rhamnosus (LGG, 106–109 CFU/mL), alone or in association with 5-fluorouracil (5-FU, 10 μM), tested against normal HaCaT cells, HT-29 colorectal adenocarcinoma and HCT-116 colorectal carcinoma cell lines. The underlying cytotoxic effect was further investigated. LGG treatment of HT-29 and HCT-116 cells caused a variety of apoptotic-related nuclear morphological changes, as revealed by DAPI staining. ELISA studies showed that LGG treatment increased caspase-3 activity and pro-apoptotic BAX protein levels while decreasing anti-apoptotic Bcl-2 protein levels and the proto-oncogene Cyclin D1. A more detailed examination of the mitochondrial function revealed that high concentrations of LGG can impair mitochondrial function in HT-29 and HCT-116 cancer cells. All of these findings suggest that LGG has a pro-apoptotic, mitochondrial-targeted, cytotoxic effect on both colon cancer cell lines studied. [ABSTRACT FROM AUTHOR]

Quercetin (Que) has been proven to enhance the chemosensitivity of multiple cancers, including colon cancer (CC). However, whether the combination of Que and 5-fluorouracil (5-FU) has a synergistic effect on drug-resistant CC cells has not previously been reported. The effect of Que (5 and 10 μg/mL) on cell vitality and apoptosis of CC and CC drug-resistant cells was examined using a cell counting kit-8 (CCK-8) and flow cytometry. After cells were treated with 5-FU (10, 40 μg/mL), Que (10 μM, 40 μM), or 5-FU in combination with Que, cell proliferation, apoptosis, oxidative stress-related factors, reactive oxygen species (ROS), and nuclear factor erythroid 2-related factor (Nrf2)/heme oxygenase-1 (HO-1) pathway-related factors were examined by colony formation assay, flow cytometry, ELISA, ROS kit, immunofluorescence assay, and Western blot. The results showed that 5-FU reduced cell viability and induced apoptosis of CC as well as 5-FU-resistant CC cells. Que further restrained the proliferation, oxidative stress-related factors (SOD, CAT, GPx, and GR), ROS production, and induced apoptosis in CC cells and 5-FU-resistant CC cells induced by 5-FU. Moreover, the combination of Que and 5-FU attenuated the Nrf2/HO-1 pathway-related marker levels in CC cells and 5-FU-resistant CC cells. Therefore, our results suggest that Que reverses 5-FU resistance in CC cells via modulating the Nrf2/HO-1 pathway.

Abstract Background Colorectal cancer is considered a potential causative agent of morbidity and death, making it a particularly dangerous malignancy. The current study aims to assess the efficacy of ferulic acid (FA) to attenuate the harmful side effect of 5-fluorouracil (5FU) in colon cancer tissues induced by 1,2-dimethylhydrazine (DMH). Results Regarding the colon tissues of male Wistar-albino rats (Rattus norvegicus), combined FA and 5FU showed the approximately normal structure of mucosa. The treated groups showed a remarkable reduction in Ki67, Ck20, and an elevation in caspase-3 and P53. There was significant upregulation of P53 in both 5FU and combined FA–5FU groups (p

Chemotherapy is the most used method after surgery in the treatment of colon cancer. Cancer cells escape the recognition mechanism of immune system cells to survive and develop chemoresistance. Therefore, the use of immunotherapy in combination with chemotherapy can increase the effectiveness of the treatment. Nanoparticles have been used clinically to increase the accumulation of therapeutics in target tissues and reduce toxicity. In this paper, nanoplexes were formed via cationic cyclodextrin polymer, 5-Fluorouracil, and Interleukin-2 based on the opposite charge interaction of macromolecules without undergoing any structural changes or losing the biological activity of Interleukin-2. Anticancer activities of nanoplexes were determined in two-dimensional and three-dimensional cell culture setups. The dual drug-loaded cyclodextrin nanoplexes diffused deeper into the spheroids and accelerated apoptosis when compared with 5-FU solutions. In the colorectal tumor-bearing animal model, survival rate, antitumor activity, metastasis, and immune response parameters were assessed using a cyclodextrin derivative, which was found to be safe based on the ALT/AST levels in healthy mice. Histomorphometric analysis showed that the groups treated with the nanoplex formulation had significantly fewer initial tumors and lung foci when compared with the control. The dual drug-loaded nanoplex could be a promising drug delivery technique in the immunochemotherapy of colorectal cancer. [ABSTRACT FROM AUTHOR]

(1) Background: Colon cancer is one of the most common cancer types, and treatment options, unfortunately, do not continually improve the survival rate of patients. With the unprecedented development of nanotechnologies, nanomedicine has become a significant direction in cancer research. Indeed, chemotherapeutics with nanoparticles (NPs) in cancer treatment is an outstanding new treatment principle. (2) Methods: Fe3O4 NPs were synthesized and characterized. Caco-2 colon cancer cells were treated during two different periods (24 and 72 h) with Fe3O4 NPs (6 μg/mL), various concentrations of 5-FU (4–16 μg/mL), and Fe3O4 NPs in combination with 5-FU (4–16 μg/mL) (Fe3O4 NPs + 5-FU). (3) Results: The MTT assay showed that treating the cells with Fe3O4 NPs + 5-FU at 16 µg/mL for 24 or 72 h decreased cell viability and increased their LDH release (p < 0.05 and p < 0.01, respectively). Furthermore, at the same treatment concentrations, total antioxidant capacity (TAC) was decreased (p < 0.05 and p < 0.01, respectively), and total oxidant status (TOS) increased (p < 0.05 and p < 0.01, respectively). Moreover, after treatment with Fe3O4-NPs + 5-FU, the IL-10 gene was downregulated and PTEN gene expression was upregulated (p < 0.05 and p < 0.01, respectively) compared with those of the control. (4) Conclusions: Fe3O4 NPs exert a synergistic cytotoxic effect with 5-FU on Caco-2 cells at concentrations below the active drug threshold levels. [ABSTRACT FROM AUTHOR]

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This study examined the gel behavior of naturally-occurring palmyra palm kernel (PPK). Due to the presence of polysaccharide in PPK hydrogels, they exhibit excellent swelling behavior in response to pH. Chemotherapeutic drug 5-fluorouracil (5-FU) was encapsulated in these gels using an equilibrium swelling technique. It was found that 5-FU had an encapsulation efficiency of up to 62%. To demonstrate the drug stability in the gels, the PPK hydrogels were characterized using fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction. The results showed that the PPK hydrogel matrix contained molecularly dispersed 5-FU drug. The PPK hydrogel exhibited a denser structure and a rough surface, according to images obtained by scanning electron microscopy. In vitro release tests were carried out at pH 1.2 (gastric fluid) and 7.4 (intestinal fluid). The efficacy of the encapsulation and the release patterns were influenced by the network topology of the PPK hydrogel. The release patterns showed that 5-FU was released gradually over a time internal of more than 12 h. The findings suggest that naturally-occurring PPK hydrogels loaded with chemotherapeutic drugs could be employed to treat colon cancer. [ABSTRACT FROM AUTHOR]

The study aimed to develop folate decorated lipid chitosan hybrid nanoparticles for targeted delivery of 5-fluorouracil in colon cancer by utilizing the overexpressed folate receptors on the surface of HT-29 and HCT 116 cancer cell lines. The developed formulations were prepared by the ionic gelation method with slight modifications. The developed formulations exhibited spherical morphology, smaller particle size (158 to 225 nm), zeta potential (32.24 to 35.95 mV), PDI (0.19 to 0.35), and high encapsulation efficiency (85.3 % to 94.2 %) with optimal physicochemical characteristics. The in vitro release showed a biphasic release pattern with an initial burst release followed by a sustained release for 48 h. Moreover, the in vitro cell line study revealed that FA-CLPN-2 exhibited an enhanced cellular uptake and greater cytotoxic effect in HT-29 and HCT 116 cell lines compared to non-targeted CLPN-2 and free drug solution due to the folate receptor facilitated endocytosis process. The in vivo toxicity study revealed the safety and biocompatibility of the developed formulations in biological systems. The stability study demonstrates the stability of the developed formulations. Overall, these results suggest that the folate decorated lipid chitosan hybrid nanoparticles could be used as a potential delivery system for tumor-targeted therapy with reduced side effects. [ABSTRACT FROM AUTHOR]

Background: 5-Fluorouracil (5-FU) represents one of the major constituents of chemotherapy combination regimens in colon cancer (CRC) treatments; however, this regimen is linked with severe adverse effects and chemoresistance. Thus, developing more efficient approaches for CRC is urgently needed to overcome these problems and improve the patient survival rate. Currently, 17β-estradiol (E2) has gained greater attention in colon carcinogenesis, significantly lowering the incidence of CRC in females at reproductive age compared with age-matched males. Aims: This study measured the effects of E2 and/or 5-FU single/dual therapies on cell cycle progression and apoptosis against human HT-29 female and SW480 male primary CRC cells versus their impact on SW620 male metastatic CRC cells. Methods: The HT-29, SW480, and SW620 cells were treated with IC50 of E2 (10 nM) and 5-FU (50 μM), alone or combined (E+F), for 48 h before cell cycle and apoptosis analyses using flow cytometry. Results: The data here showed that E2 monotherapy has great potential to arrest the cell cycle and induce apoptosis in all the investigated colon cancer cells, with the most remarkable effects on metastatic cells (SW620). Most importantly, the dual therapy (E+F) has exerted anti-cancer activities in female (HT-29) and male (SW480) primary CRC cells by inducing apoptosis, which was preferentially provoked in the sub-G1 phase. However, the dual treatment showed the smallest effect in SW620 metastatic cells. Conclusion: this is the first study that demonstrated that the anti-cancer actions of 17β-estradiol and 5-Fluorouracil dual therapy were superior to the monotherapies in female and male primary CRC cells; it is proposed that this treatment strategy could be promising for the early stages of CRC. At the same time, 17β-estradiol monotherapy could be a better approach for treating the metastatic forms of the disease. Nevertheless, additional investigations are still required to determine their precise therapeutic values in CRC. [ABSTRACT FROM AUTHOR]

Abstract Background In the current study, folic acid-conjugated PEG-PCL-PEG triblock copolymer were synthesized and loaded with 5-fluorouracil and magnetite nanoparticles (5-FU-SPION-PEG-PCL-PEG-FA) for targeted delivery of drug to HT29 human colon cancer cells and CT26 mouse colon cancer model. The nanoparticles were synthesized and characterized by nuclear magnetic resonance spectroscopy (NMR) and transmission electron microscopy (TEM). The cellular uptake of nanoparticles was assessed in vitro (on HUVEC and HT29) and in vivo (on CT26 colon tumor tissues). The cytotoxic effect of nanoparticles was assessed on human colon cell lines (HT29, Caco-2, HTC116, and SW480) and normal HUVEC cells. In addition, antitumor effects of nanoparticles were investigated based on tumor volume, survival time and protein expression of Bax and Bcl-2 on CT26 tumor-bearing BALB/c mice. Results Characterization of nanoparticles showed 5-FU-SPION-PEG-PCL-PEG-FA (5-FU-NPs-FA) nanoparticles had spherical shape with hydrodynamic diameter of 85 nm. The drug-release profile exhibited sustained pH-responsive release with cumulative release reaching approximately 23% after 24 h. Cellular uptake studies revealed that HT29 cancer cells absorb higher amount of 5-FU-NPs-FA as compared to HUVEC normal cells (P

5-Fluorouracil (5-FU) is frequently used to treat colorectal cancer (CRC), but its clinical application is limited by its toxicity. Natural compounds have been combined with chemotherapeutic drugs to reduce chemotherapy-related toxicity. Diosmetin, a natural flavonoid, has demonstrated anticancer effects against CRC. This study investigated diosmetin's potential in combination with 5-FU using a murine model of HCT-116 colon cancer xenografts in nu/nu nude mice. HCT-116 cells were injected into the right flanks of mice, and once tumors reached a size of 50 mm3, the mice were treated with diosmetin (100 mg/kg), 5-FU (30 mg/kg), or a combination of both at two dose levels (100 + 30 mg/kg and 50 + 15 mg/kg) for 4 weeks. Blood and tumors were collected on the final day for further analysis. Mice treated with the higher combination dose exhibited the smallest tumor volume (330.91 ± 88.49 mm3). Biochemistry and histology analysis showed no toxicity or abnormalities in the liver, kidney, and heart with the combination therapy. Immunohistochemistry results revealed a notable reduction in the proliferation marker (Ki67) and inflammation marker (TLR4) in tumors from high-dose combination-treated mice. Moreover, immunofluorescence data indicated increased levels of apoptotic markers (Bax, Caspase-3, p53, p21) and downregulation of anti-apoptotic protein (Bcl-2) in the high-dose combination group. The findings suggest that 100 mg/kg of diosmetin combined with 30 mg/kg 5-FU significantly reduced tumor volume and had a less toxic effect on the heart compared to 5-FU monotherapy. • Diosmetin (100 mg/kg) with 5-FU (30 mg/kg) significantly suppressed HCT-116 colon tumor growth in nude mice model. • Biochemical and histological tests indicated minimal toxicity in the liver, kidney, and heart with the combination therapy. • Immunohistochemistry revealed reduced Ki67 and TLR4 markers in tumor tissues with the high-dose combination treatment. • Immunofluorescence showed increased apoptotic proteins and decreased anti-apoptotic protein (Bcl-2) in treated mice. • Diosmetin with 5-FU reduced tumor volume and caused less heart toxicity compared to 5-FU monotherapy. [ABSTRACT FROM AUTHOR]

Colon cancer is a significant health problem worldwide as it is one of the most common and deadliest cancers. The standard approach for the treatment of colon cancer is 5-fluorouracil (5-FU) based chemotherapy, which is limited by the development of resistance to this drug. Therefore, our study aimed to establish 5-FU resistance in SW-480 and HT-29 colon cancer cells and to precisely determine the molecular mechanisms and biomarkers that contribute to its development, both after short-term exposure and in cells with already developed resistance (SW-480-5FUR and HT-29-5FUR). The expression of various molecules involved in the different mechanisms of resistance development was monitored at the gene (qPCR) and protein (immunocytochemistry) levels. Based on the obtained results, alterations in the 5-FU anabolic pathway, biotransformation, drug efflux, mismatch repair, and apoptosis process together contributed to the development of 5-FU resistance in SW-480 and HT-29 colon cancer cells. In addition, UMPS , ABCC1 , ABCC5 , and MLH1 , as well as the disturbed ratio of pro-apoptotic BAX and anti-apoptotic BCL2 , should be taken into consideration as potential targets for the discovery of 5-FU resistance-related biomarkers in colon cancer cells. We suggest that future investigations focus on further validation of these findings by additional in vitro and in vivo testing, which is a limitation of our study. [Display omitted] [ABSTRACT FROM AUTHOR]

5-Fluorouracil (5-Fu) is a widely applied anti-cancer agent against colorectal cancer (CRC), yet a number of CRC patients have developed resistance to 5-Fu-based chemotherapy. The epidermal growth factor receptor (EGFR) is recognized as an oncogene that promotes diverse cancer progresses. In addition, long noncoding RNAs (lncRNAs) are essential regulators of cancers. Here we report that EGFR and lncRNA-FGD5-AS1 promoted 5-Fu resistance of CRC. By establishing the 5-Fu-resistant CRC cell line, we detected that EGFR, FGD5-AS1, and glucose metabolism were significantly elevated in 5-Fu-resistant CRC cells. A microRNA-microarray analysis revealed that miR-330-3p functions as a downstream effector of FGD5-AS1. FGD5-AS1 directly sponged miR-330-3p to form a competing endogenous RNA (ceRNA) network, leading to inhibition of miR-330-3p expression. Furthermore, bioinformatics analysis revealed that Hexokinase 2 (HK2) was a potential target of miR-330-3p, which was validated by luciferase assay. Rescue experiments demonstrated that FGD5-AS1 promotes glycolysis through modulating the miR-330-3p-HK2 axis, leading to 5-Fu resistance of CRC cancer cells. Finally, in vitro and in vivo xenograft experiments consistently demonstrated that inhibition of EGFR by the specific inhibitor erlotinib effectively enhanced the anti-tumor toxicity of 5-Fu by targeting the EGFR-FGD5-AS1-miR-330-3p-HK2 pathway. In summary, this study demonstrates new mechanisms of the EGFR-modulated 5-Fu resistance through modulating the noncoding RNA network, contributing to development of new approaches against chemoresistant CRC.

Abstract Background The purpose of the present study was to evaluate the efficacy of chemo-magnetic hyperthermia (MH), a combination of alternating magnetic field (AMF) and superparamagnetic nanoparticles (SPIONs) coated with Polyethylene glycol-Poly(butyl acrylate)-Polyethylene glycol (PEG-PBA-PEG) carrying 5-Fluorouracil (5-Fu), at inducing apoptosis in the human cancer cell lines HT29 and HCT116. This process can be mediated by alterations in the expression of apoptotic effector proteins, including Bax, Bcl-2, cleaved caspase 3&9, and cleaved PARP, which are involved in the intrinsic pathway of apoptosis. For this purpose, the cells were cultured as monolayers. Then both cell lines were treated with 5-Fu/magnetic nanoparticles and magnetic hyperthermia. Finally, the effect of treatment on cancer cells was determined by Western blot analysis and flow cytometry. Results Our results showed that combined chemo-magnetic thermotherapy significantly increased the apoptosis in colon cancer cells compared to chemotherapy or hyperthermia alone (P

Colorectal cancer was inducted in Wister rats using titanium dioxide nanoparticles (TiO2NPs) and dimethylhydrazine (DMH) and treatment using 5-fluorouracil (5-FU) and curcumin (CUR), individually and following a synergistic approach. Compatibility studies are evaluated by using FT-IR spectra analysis, and Vero cell lines as well as HCT-116 cell lines are used for evaluating the synergistic approach. It was then followed by induction of colorectal cancer in rats for 70 days and treatment using 5-FU and CUR with pectin coating (individually and in combination) for 28 days. The reports state that 5-FU and CUR combination was found to be compatible. The synergistic effect was evaluated for1:1, 1:2, 1:4, and 2:1 ratio of 5-FU:CUR, where 1:4 ratio shows a CI50 value of 0.853, selected further for the animal studies. The 1:4 ratio of 5-FU and CUR (50:200) shows to be effective for the treatment of colorectal cancer within 28 days, proven using histopathology report, bodyweight analysis, and hematological reports. 5-FU and CUR (1:4) ratio with pectin coating was proven effective for the treatment of colorectal cancer induced by TiO2NPs with DMH and was found to produce a synergistic effect. [ABSTRACT FROM AUTHOR]

Cancer remains a leading cause of death worldwide and, even though several advances have been made in terms of specific treatment, the late-stage detection and the associated side effects of the conventional drugs sustain the search for better treatment alternatives. Probiotics are live microorganisms that have been proven to possess numerous health benefits for human hosts, including anticancer effects. In the present study, the in vitro effect of the association of two probiotic strains (PBT), Lactobacillus sporogenes and Clostridium butyricum, were tested against colon (HT-29 and HCT 116), lung (A549), and liver (HepG2) cancer cell lines, alone or in combination with 5-fluorouracil (5FU). Moreover, the underlying mechanism of PBT and PBT-5FU against the HT-29 cell line was evaluated using the Hoechst 33342 staining, revealing characteristic apoptotic modifications, such as chromatin condensation, nuclear fragmentation, and membrane blebbing. Furthermore, the increase in the expression of pro-apoptotic Bax, Bid, Bad, and Bak proteins and the inhibition of the anti-apoptotic Bcl-2 and Bcl-XL proteins were recorded. Collectively, these findings suggest that the two strains of probiotic bacteria, alone or in association with 5FU, induce apoptosis in colon cancer cells and may serve as a potential anticancer treatment. [ABSTRACT FROM AUTHOR]

Abstract Background In recent years, targeted drug delivery strategies have received special attention from the scientific world due to advantages such as more effective therapy and reduction of side effects. The principle of operation is delayed excretion from the bloodstream of the drug delivery system compared to the drug itself, as well as facilitated penetration into diseased cells thanks to the use of ligands recognized by appropriate receptors. Particularly interesting drug carriers are amphiphilic copolymers that form nano-sized micelles with a drug, which can release the drug at a specific place in the body under the influence of appropriate stimuli. Results We describe the synthesis of the diblock polymer, poly(2-hydroxyethyl acrylate)-b-poly(N-vinylcaprolactam) using RAFT/MADIX (Reversible Addition-Fragmentation chain Transfer/MAcromolecular Design by Interchange of Xanthate) controlled polymerization affording polymers with good dispersity according to SEC (Size-Exclusion Chromatography). Some post-modifications of the polymer with folic acid were then performed as evidenced by NMR (Nuclear Magnetic Resonance), UV–Vis (UltraViolet–Visible) and FT-IR (Fourier-Transform Infrared) spectroscopy, and TGA (ThermoGravimetric Analysis). The formation of stable micellar systems from polymers with and without the drug, 5-fluorouracil, was confirmed by DLS (Dynamic Light Scattering) and zeta potential measurements, and TEM (Transmission Eelectron Microscopy) imaging. Finally, the cloud point of the polymers was investigated, which turned out to be close to the temperature of the human body. Most importantly, these micellar systems have been explored as a drug delivery system against colon cancer, showing increased cytotoxicity compared to the drug alone. This effect was achieved due to the easier cellular uptake by the interaction of folic acid and its receptors on the surface of cancer cells. Conclusions The presented results constitute a solid foundation for the implementation of a nano-sized drug delivery system containing folic acid for practical use in the treatment of drug-resistant cancer, as well as more effective therapy with fewer side effects. Graphical Abstract

Introduction: 5-fluorouracil (5-FU) is the most widely used chemotherapeutic drug in treating colorectal cancer. However, its toxicity to normal tissues and tumour resistance are the main hurdles to efficient cancer treatment. MiR27-a promotes the proliferation of colon cancer cells by stimulating the Wnt/β-catenin pathway. The present study was conducted to examine whether quercetin (Q) combined with 5-FU improves the anti-proliferative effect of 5-FU on HCT-116 and Caco-2 cell lines through detection of the miR-27a/Wnt/β-catenin signalling pathway. Material and methods: Cell viability in HCT-116 and Caco-2 cell lines following quercetin and 5-FU treatment alone and in combination for 48 hours was determined using the MTT assay. The flow cytometry, quantitative real-time polymerase chain reaction, and ELISA techniques were used. Results: Our results showed that combination of quercetin and 5-FU exhibited greater cytotoxic efficacy than did 5-FU alone. Co-administration of both drugs either in combination 1 (1: 1 Q: 5-FU) or in combination 2 (1: 0.5 Q: 5-FU) enhanced apoptosis in HCT-116 and Caco-2 cells compared with 5-FU alone and significantly inhibited the expression of miR-27a, leading to upregulation of secreted frizzled-related protein 1 and suppression of Wnt/β-catenin signalling, which was confirmed by a significant decrease in cyclin D1 expression. Conclusions: Quercetin strongly enhanced 5-FU sensitivity via suppression of the miR-27a/Wnt/β-catenin signalling pathway in CRC, which advocates further research of this combination with the lower dose of 5-FU. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the anticancer effects of biosynthesized silver nanoparticles (Vv-AgNPs) from grape (Vitis vinifera L.) seed aqueous extract, alone or in combination with 5-Fluorouracil (5-FU) on HT-29 cell line. Vv-AgNPs were characterized by techniques such as UV–vis spectrophotometer (surface plasmon peak 454 nm), scanning electron microscopy (SEM), and energy-dispersive X-ray spectroscopy (EDX). HT-29 cells were treated with different concentrations (0–80 μg/mL for MTT) and (0–20 μg/mL for BrdU) of Vv-AgNPs alone and combined with (200 μg/mL) 5-FU for 72 h. The cytotoxic effects were analyzed by [3-(4,5-dimethylthiazol-2- yl)-2,5-diphenyl tetrazolium bromide] (MTT) assay (IC50 values 13.74 and 5.35 μg/mL, respectively). Antiproliferative effects were examined 5-bromo-2'-deoxyuridine (BrdU) assay (IC50 values 9.65 and 5.00 μg/mL, respectively). Activation of caspase-3 and protein expression levels of p53 were determined by Western blotting analysis. It was observed that Vv-AgNPs significantly increased the cleavage of the proapoptotic proteins caspase 3 and obviously enhanced the expression of p53 in a dose-dependent manner. The increased amount of total oxidant status (TOS) in the 10 μg/mL Vv-AgNPs + 5-FU treatment group, despite the increasing amount of total antioxidant status (TAS), caused an increase in Oxidative Stress Index (OSI) compared to the control. In this study, it has been shown in vitro that the use of successfully biosynthesized Vv-AgNPs in combination with 5-FU exhibits synergistic cytotoxic, antiproliferative, apoptotic, and oxidative effects against HT-29 cell line. [ABSTRACT FROM AUTHOR]

Cancer mortality is mainly due to metastasis. Therefore, searching for new therapeutic agents suppressing cancer cell migration is crucial. Data from human studies regarding effects of anthocyanins on cancer progression, however, are scarce and it is unclear whether physiological concentrations of anthocyanins and their metabolites reduce cancer cell migration in vivo. In addition, interactions with chemotherapeutics like 5-fluorouracil (5-FU) are largely unknown. Thus, we combined a placebo-controlled, double-blinded, cross-over study with in vitro migration studies of colon cancer cell lines to examine the anti-migratory effects of plasma-isolated anthocyanins and their metabolites (PAM). Healthy volunteers (n = 35) daily consumed 0.33 L of an anthocyanin-rich grape/bilberry juice and an anthocyanin-depleted placebo juice for 28 days. PAM were isolated before and after intervention by solid-phase extraction. HT-29 and Caco-2 cells were incubated with PAM in a Boyden chamber. Migration of HT-29 cells was significantly inhibited by PAM from juice but not from placebo. In contrast, Caco-2 migration was not affected. Co-incubation with 5-FU and pooled PAM from volunteers (n = 10), which most effectively inhibited HT-29 migration, further reduced HT-29 migration in comparison to 5-FU alone. Therefore, PAM at physiological concentrations impairs colon cancer cell migration and may support the effectiveness of chemotherapeutics. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer is considered a potential causative agent of morbidity and death, making it a particularly dangerous malignancy. The current study aims to assess the efficacy of ferulic acid (FA) to attenuate the harmful side effect of 5-fluorouracil (5FU) in colon cancer tissues induced by 1,2-dimethylhydrazine (DMH). Results: Regarding the colon tissues of male Wistar-albino rats (Rattus norvegicus), combined FA and 5FU showed the approximately normal structure of mucosa. The treated groups showed a remarkable reduction in Ki67, Ck20, and an elevation in caspase-3 and P53. There was significant upregulation of P53 in both 5FU and combined FA–5FU groups (p < 0.001 and p < 0.00001, respectively). Conclusions: The present results revealed a potential role of the combined therapy by 5FU and FA in the suppression of colon cancer induced by DMH by upregulation of apoptosis with the clear effect of FA in attenuating the side effects of 5FU on the normal cells. [ABSTRACT FROM AUTHOR]

Even though various treatment methods are available for cancer, the death curve is not reducing. The diagnosis of cancer at the fourth stage and drug resistance are the leading reasons for treatment failure and lower survival rates. In this review article, we summarize the possible pitfalls during cancer treatment in general, which mainly include multidrug resistance, and propose a hypothesis for colorectal cancer specifically. We also evaluate multidrug resistance in cancer in general and colorectal cancer in particular and hypothesize a concept based on combination therapy with 5-fluorouracil, curcumin, and lipids for the possible management of colorectal cancer. In addition, a hypothetical approach, combining a synthetic agent and a natural chemotherapeutic agent, to treating colorectal cancer is also discussed. This hypothesis could improve the management of colorectal cancer. [ABSTRACT FROM AUTHOR]

Objective To construct a 5-fluorouracil (5-FU)-resistant colon cancer cell line, and to investigate the role of stearoyl CoA desaturase 1 (SCD1) in the resistance of colon cancer cells to 5-FU. Methods Drug resistance to 5-FU was induced in colon cancer cell line HCT116 by increasing the concentration intermittently and repeated inducing and screening with high concentration to produce drug-resistant cell line HCT116/5FU. The survival rates and half maximal inhibitory concentration (IC50) were measured by CCK-8 assay in HCT116, HCT116/5FU, HCT116-Control and HCT116-OE-SCD1 cells after the treatment of 5-FU. Immunohistochemical assay was employed to measure the expression of SCD1 after the fabrication of colon cancer and paracancerous tissue chips. Quantitative PCR and Western blotting were applied to detect the expression of SCD1. CCK-8 assay, plate clone formation and crystal violet staining were used to detect cell survival status. The apoptotic rates were detected by AnnexinV-FITC/PI double staining. HCT116-Control and HCT116-OE-SCD1 subcutaneous xenograft models in nude mice were established to observe the effect of SCD1 on tumor growth. Western blotting was carried out to detect the expression of apoptosis-related proteins. Results The IC50 value of 5-FU was 0.90±0.06 μg/mL in HCT116 cells, and 15.02±0.81 μg/mL in HCT116/5FU cells, with a multiple of resistance about 16.7 times. The expression of SCD1 was higher in drug resistant colon cancer tissues than in common colon cancer tissues and corresponding paracancerous tissues. And its expression level was also higher in HCT116/5FU cells than HCT116 cells. Overexpression of SCD1 reduced the apoptotic rate of colon cancer cells(P < 0.01). Xenograft nude mouse model indicated that SCD1 overexpression enhanced the resistance of colon cancer cells to 5-FU. After 48 h of 5-FU treatment, the expression of bcl-2 and caspase3 were lower in HCT116-OE-SCD1 group than HCT116-Control group(P < 0.01). Conclusion The 5-FU-resistant model of colon cancer HCT116/5FU cells is successfully established. SCD1 promotes the resistance to 5-FU in colon cancer cells

Herein, 5-fluorouracil and shikonin (extracted from Fusarium tricinctum) were loaded in chitosan/pectin nanoparticle (CS/PEC-NPs), prepared by blending (B-CS/PEC-NPs) and coating (C-CS/PEC-NPs) methods. The nanoparticles characterized by Fourier Transform Infrared (FTIR), X-ray diffraction (XRD), Energy-dispersive X-ray (EDX), Scanning Electron Microscope (SEM) and Differential Light Scattering (DLS). Then, some properties of the nanoparticles such as drug release rate and the nanoparticles cytotoxicity were studied. The FTIR, XRD, EDX, SEM and DLS results showed that the nanoparticles synthesized properly with an almost spherical morphology, an average size of 82–93 nm for B-CS/PEC-NPs, an average diameter of below 100 nm (mostly 66–89 nm) for C-CS/PEC-NPs, and hydrodynamic diameter of 310–817 nm. The drug release results indicated the lower release rate of drugs for B-CS/PEC-NPs relative to C-CS/PEC-NPs at different pHs, high release rate of drugs for the nanoparticles in the simulated large intestinal fluids containing pectinase, and Korsmeyer-Peppas model for release of the drugs. The results showed more cytotoxicity of B-CS/PEC-NPs containing drugs, especially B-CS/PEC-NPs containing both drugs (B-CS/PEC/5-FU/SHK-NPs) after treating with pectinase (IC 50 of 18.6 μg/mL). In conclusion, despite the limitation of C-CS/PEC-NPs for simultaneous loading of hydrophilic and hydrophobic drugs, B-CS/PEC-NPs showed suitable potency for loading and targeted delivery of the drugs. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most prevalent fatal neoplasias worldwide. Despite efforts to improve the early diagnosis of CRC, the mortality rate of patients is still nearly 50%. The primary treatment strategy for CRC is surgery, which may be accompanied by chemotherapy and radiotherapy. The conventional and first-line chemotherapeutic agent utilized is 5-fluorouracil (5FU). However, it has low efficiency. Combination treatment with leucovorin and oxaliplatin or irinotecan improves the effectiveness of 5FU therapy. Unfortunately, most patients develop drug resistance, leading to disease progression. Here, we evaluated the effect of a potential alternative adjuvant treatment for 5FU, helminth-derived Taenia crassiceps (TcES) molecules, on treating advanced colitis-associated colon cancer. The use of TcES enhanced the effects of 5FU on established colonic tumors by downregulating the expression of the immunoregulatory cytokines, Il-10 and Tgf-β , and proinflammatory cytokines, Tnf-α and Il-17a , and reducing the levels of molecular markers associated with malignancy, cyclin D1, and Ki67, both involved in apoptosis inhibition and the signaling pathway of β-catenin. TcES+5FU therapy promoted NK cell recruitment and the release of Granzyme B1 at the tumor site, consequently inducing tumor cell death. Additionally, it restored P53 activity which relates to decreased Mdm2 expression. In vitro assays with human colon cancer cell lines showed that therapy with TcES+5FU significantly reduced cell proliferation and migration by modulating the P53 and P21 signaling pathways. Our findings demonstrate, for the first time in vivo, that helminth-derived excreted/secreted products may potentiate the effect of 5FU on established colon tumors. [Display omitted] • Molecules from T. Crassiceps improve the 5FU activity in CAC model. • TcES down regulates proliferation and malignancy markers Ki67 and Cyclin D1. • Granzyme B1 is upregulated in TcES+5FU treatment. • Combinatory effect TcES+5FU improve apoptosis through up-regulation P53. [ABSTRACT FROM AUTHOR]

Background: In the current study, folic acid-conjugated PEG-PCL-PEG triblock copolymer were synthesized and loaded with 5-fluorouracil and magnetite nanoparticles (5-FU-SPION-PEG-PCL-PEG-FA) for targeted delivery of drug to HT29 human colon cancer cells and CT26 mouse colon cancer model. The nanoparticles were synthesized and characterized by nuclear magnetic resonance spectroscopy (NMR) and transmission electron microscopy (TEM). The cellular uptake of nanoparticles was assessed in vitro (on HUVEC and HT29) and in vivo (on CT26 colon tumor tissues). The cytotoxic effect of nanoparticles was assessed on human colon cell lines (HT29, Caco-2, HTC116, and SW480) and normal HUVEC cells. In addition, antitumor effects of nanoparticles were investigated based on tumor volume, survival time and protein expression of Bax and Bcl-2 on CT26 tumor-bearing BALB/c mice. Results: Characterization of nanoparticles showed 5-FU-SPION-PEG-PCL-PEG-FA (5-FU-NPs-FA) nanoparticles had spherical shape with hydrodynamic diameter of 85 nm. The drug-release profile exhibited sustained pH-responsive release with cumulative release reaching approximately 23% after 24 h. Cellular uptake studies revealed that HT29 cancer cells absorb higher amount of 5-FU-NPs-FA as compared to HUVEC normal cells (P < 0.05). In addition, 5-FU-NPs-FA was found to be more antitumor efficient in comparison to free 5-FU based on Bax/Bcl2 ratio, survival rate of tumoral mouse and inhibitory tumor volume (P < 0.05). Conclusions: The results suggested that 5-FU-NPs-FA could be considered as promising sustained drug delivery platform for in vitro and in vivo conditions, which may provide selective treatment of tumor cancer cells. Graphical Abstarct: [ABSTRACT FROM AUTHOR]

β-Boswellic acid (β-BA), a potent NF-kB signaling pathway inhibitor, has shown synergistic anti-cancerous activity (NCT03149081, NCT00243022 and NCT02977936) in various clinical trials as complementary therapies. The study has been conducted to investigate the effect and efficacy of 2-pyridin-4-yl methylene β-boswellic acid (PMBA) and 5-Flourouracil (5-FU) in combination therapy for the treatment of KRAS mutant colon cancer. Analysis of isobologram showed synergistic combination index (CI > 1) of PMBA and 5-FU against the HCT-116G13D and SW-620G12V cell lines. The growth-inhibiting PMBA also caused apoptosis mediating effects with dose-dependent increase in caspase-3 activity, while inhibiting the formation of colonies in combination with 5-FU. As evident, PMBA affected colorectal 3D CSC properties including the ability to self-renew along with the expression of multi-drug resistance genes, viz., ABCB1, ABCC1 and ALDH1A1, ALDH1A2, ALDH1A3, ALDH3A1, and CSC markers like CD44, CD166, EPCAM, OCT-4, SOX-2, and NANOG compared with those in 2D model explaining the expression pattern of oncogenic KRASG13D, G12V mutation. When examined for plasma level of PMBA (20 mg) and PMBA+5-FU (20 + 40 mg), a time-dependent increase in the level of the drug (5-FU) was detected, indicating its absorption and bioavailability with excellent half-life of the PMBA for both routes of administration (IV and Oral), thereby indicating a new adjuvant therapy for KRAS mutant colon cancer.

Background: Drug-drug interaction (DDI), which can occur at the pharmacokinetics and/or the pharmacodynamics (PD) levels, can increase or decrease the therapeutic or adverse response of a drug itself or a combination of drugs. Cancer patients often receive, along their antineoplastic agents, antibiotics such as ß-lactams to treat or prevent infection. Despite the narrow therapeutic indices of antibiotics and antineoplastic agents, data about their potential interaction are insufficient. 5-fluorouracil (5-FU), widely used against colon cancer, is known for its toxicity and large intra- and inter- individual variability. Therefore, knowledge about its interaction with antibiotics is crucial.Methods: In this study, we evaluated at the PD levels, against HCT-116 colon cancer cells, DDI between 5-FU and several ß-lactams (ampicillin, benzypenicillin, piperacillin, meropenem, flucloxacillin, ceftazidime (CFT), and cefepime (CFP)), widely used in intensive care units. All drugs were tested at clinically achieved concentrations. MTT assay was used to measure the metabolic activity of the cells. Cell cycle profile and apoptosis induction were monitored, in HCT-116 and DLD-1 cells, using propidium iodide staining and Caspase-3/7 activity assay. The uptake of CFT and CFP by the cells was measured using LC-MS/MS method.Results: Our data indicate that despite their limited uptake by the cells, CFT and CFP (two cephalosporins) antagonized significantly 5-FU-induced S-phase arrest (DLD-1 cells) and apoptosis induction (HCT-116 cells). Remarkably, while CFP did not affect the proliferation of colon cancer cells, CFT inhibited, at clinically relevant concentrations, the proliferation of DLD-1 cells via apoptosis induction, as evidenced by an increase in caspase 3/7 activation. Unexpectedly, 5-FU also antagonized CFT's induced cell death in DLD-1 cells.Conclusion: This study shows that CFP and CFT have adverse effects on 5-FU's action while CFT is a potent anticancer agent that inhibits DLD-1 cells by inducing apoptotic cell death. Further studies are needed to decipher the mechanism(s) responsible for CFT's effects against colon cancer as well as the observed antagonism between CFT, CFP, and 5-FU with the ultimate aim of translating the findings to the clinical settings. [ABSTRACT FROM AUTHOR]

Background: The purpose of the present study was to evaluate the efficacy of chemo-magnetic hyperthermia (MH), a combination of alternating magnetic field (AMF) and superparamagnetic nanoparticles (SPIONs) coated with Polyethylene glycol-Poly(butyl acrylate)-Polyethylene glycol (PEG-PBA-PEG) carrying 5-Fluorouracil (5-Fu), at inducing apoptosis in the human cancer cell lines HT29 and HCT116. This process can be mediated by alterations in the expression of apoptotic effector proteins, including Bax, Bcl-2, cleaved caspase 3&9, and cleaved PARP, which are involved in the intrinsic pathway of apoptosis. For this purpose, the cells were cultured as monolayers. Then both cell lines were treated with 5-Fu/magnetic nanoparticles and magnetic hyperthermia. Finally, the effect of treatment on cancer cells was determined by Western blot analysis and flow cytometry. Results: Our results showed that combined chemo-magnetic thermotherapy significantly increased the apoptosis in colon cancer cells compared to chemotherapy or hyperthermia alone (P < 0.05). Up-regulation of Bax, cleaved caspase 3&9, and cleaved PARP proteins was indicative of apoptosis induction in cancer cells, which are involved in the intrinsic pathway of apoptosis. Conclusions: This study demonstrates that localized hyperthermia was able to significantly trigger the 5-Fu release and inhibit cell viability, which, due to the synchronization of hyperthermia and chemotherapy, exacerbated the damage of cancer cells. [ABSTRACT FROM AUTHOR]