RESUMO
The defeat of cancer is still a challenge due to the existence of cancer stem cells (CSCs) because they resist conventional chemotherapy via multifactor regulated mechanisms. Consequently, one-dimensional action toward CSCs cannot work. Herein, we used rationally designed hybrid nanoparticles as a combined cancer therapy, hoping to form a multidimensional control network. In this paper, gold/silver alloy nanoparticle decorated camptothecin nanocrystals were formulated according to complementary anti-CSC mechanisms from gold, silver, and organic drug. This smart drug formulation could combine chemotherapy and thermotherapy, target different tumor sites, and demonstrate versatile toxicity profiles from each component. Major results indicated that this nanosystem demonstrated indiscriminately effective cytotoxic/proapoptotic/necrotic activity against bulk MCF-7 cells and their CSC subpopulation, in particular under laser ablation. Moreover, this nanosystem displayed enhanced antineoplastic activity against CSC spheroids, resulting in a significant reduction in their number and size, that is, their self-renewal capacity. All the results indicated that CSCs upon treatment of these new hybrid nanoparticles underwent reduced stemness and conversion from the original quiescent state and recovered their sensitivity toward chemotherapy. The relevant anticancer mechanism was ascribed to NIR-pH dual responsive drug release, synergistic/combined thermo-chemotherapy of organic drug and inorganic alloy nanoparticles, enhanced cellular uptake mediated by alloy nanoparticles, and Ag+-induced biomembrane damage. This thermo-chemotherapy platform provides a new combinatorial strategy for inorganic and organic agents in the complete elimination of CSCs.
Assuntos
Antineoplásicos , Nanopartículas , Neoplasias , Humanos , Camptotecina/farmacologia , Prata , Ouro/química , Antineoplásicos/farmacologia , Nanopartículas/química , Células-Tronco Neoplásicas , Ligas/farmacologia , Linhagem Celular Tumoral , Neoplasias/patologiaRESUMO
Attenuation of camptothecin (CPT) productivity by fungi with preservation and subculturing is the challenge that halts fungi to be an industrial platform of CPT production. Thus, screening for novel endophytic fungal isolates with metabolic stability for CPT production was the objective. Catharanthus roseus is one of the medicinal plants with diverse bioactive metabolites that could have a plethora of novel endophytes with unique metabolites. Among the endophytes of C. roseus, Aspergillus terreus EFBL-NV OR131583.1 had the most CPT producing potency (90.2 µg/l), the chemical identity of the putative CPT was verified by HPLC, FT-IR, NMR and LC-MS/MS. The putative A. terreus CPT had the same molecular mass (349 m/z), and molecular fragmentation patterns of the authentic one, as revealed from the MS/MS analyses. The purified CPT had a strong activity against MCF7 (5.27 µM) and UO-31 (2.2 µM), with a potential inhibition to Topo II (IC50 value 0.52 nM) than Topo 1 (IC50 value 6.9 nM). The CPT displayed a high wound healing activity to UO-31 cells, stopping their metastasis, matrix formation and cell immigration. The purified CPT had a potential inducing activity to the cellular apoptosis of UO-31 by ~ 17 folds, as well as, arresting their cellular division at the S-phase, compared to the control cells. Upon Plackett-Burman design, the yield of CPT by A. terreus was increased by ~ 2.6 folds, compared to control. The yield of CPT by A. terreus was sequentially suppressed with the fungal storage and subculturing, losing ~ 50% of their CPT productivity by 3rd month and 5th generation. However, the productivity of the attenuated A. terreus culture was completely restored by adding 1% surface sterilized leaves of C. roseus, and the CPT yield was increased over-the-first culture by ~ 3.2 folds (315.2 µg/l). The restoring of CPT productivity of A. terreus in response to indigenous microbiome of C. roseus, ensures the A. terreus-microbiome interactions, releasing a chemical signal that triggers the CPT productivity of A. terreus. This is the first reports exploring the potency of A. terreus, endophyte of C. roseus" to be a platform for industrial production of CPT, with an affordable sustainability with addition of C. roseus microbiome.
Assuntos
Catharanthus , Cromatografia Líquida , Endófitos , Espectroscopia de Infravermelho com Transformada de Fourier , Espectrometria de Massas em Tandem , Isomerases , Camptotecina/farmacologia , Ciclo CelularRESUMO
BACKGROUND: Colorectal cancer (CRC) is one of the most common types of cancer. This disease arises from gene mutations and epigenetic alterations that transform colonic epithelial cells into colon adenocarcinoma cells, which display a unique gene expression pattern compared to normal cells. Specifically, CRC cells exhibit significantly higher expression levels of genes involved in DNA repair or replication, which is attributed to the accumulation of DNA breakage resulting from rapid cell cycle progression. PURPOSE: This study aimed to investigate the in vivo effects of caffeine on CRC cells and evaluate its impact on the sensitivity of these cells to irinotecan, a topoisomerase I inhibitor widely used for CRC treatment. METHODS: Two CRC cell lines, HCT116 and HT29, were treated with irinotecan and caffeine. Western blot analysis assessed protein expression levels in caffeine/irinotecan-treated CRC cells. Immunofluorescence staining determined protein localization, measured DNA breaks, and explored the effects of DNA damage reagents during cell cycle progression and flow cytometry analysis was used to measure cell viability. Fiber assays investigated DNA synthesis in DNA-damaged cells during S-phase, while the comet assay assessed DNA fragmentation caused by DNA breaks. RESULTS: Our findings demonstrated that the combination of irinotecan and caffeine exhibits a synergistic effect in suppressing CRC cell proliferation and inducing cell death. Compared to treatment with only irinotecan or caffeine, the combined irinotecan and caffeine treatment was more effective in inducing DNA lesions by displacing RAD51 from DNA break sites and inhibiting DNA repair progression, leading to cell cycle arrest. This combination also resulted in more severe effects, including DNA fragmentation and mitotic catastrophe. CONCLUSION: Caffeine could enhance the effectiveness of an existing drug for CRC treatment despite having little impact on the cell survival rate of CRC cells. Our findings suggest that the beneficial adjuvant effects of caffeine may not only be applicable to CRC but also to various other types of cancers at different stages of development.
Assuntos
Adenocarcinoma , Neoplasias do Colo , Neoplasias Colorretais , Humanos , Irinotecano/farmacologia , Irinotecano/uso terapêutico , Cafeína/farmacologia , Neoplasias do Colo/patologia , Camptotecina/farmacologia , Adenocarcinoma/tratamento farmacológico , DNA/uso terapêutico , Neoplasias Colorretais/patologia , Linhagem Celular TumoralRESUMO
Fungal producing potency of camptothecin (CPT) raise the hope for their usage to be a platform for industrial production of CPT, nevertheless, attenuation of their productivity of CPT with the subculturing and preservation is the challenge. So, screening for novel endophytic fungal isolates with a reliable CPT-biosynthetic stability was the objective. Among the isolated endophytic fungi from the tested medicinal plants, Aspergillus terreus OQ642314.1, endophyte of Cinnamomum camphora, exhibits the highest yield of CPT (89.4 µg/l). From the NMR, FT-IR and LC-MS/MS analyses, the extracted CPT from A. terreus gave the same structure and molecular mass fragmentation pattern of authentic CPT (349 m/z). The putative CPT had a significant activity against MCF7 (0.27 µM) and HEPG-2 (0.8 µM), with a strong affinity to inhibits the human Topoisomerase 1 activity (IC50 0.362 µg/ml) as revealed from the Gel-based DNA relaxation assay. The purified CPT displayed a strong antimicrobial activity for various bacterial (E. coli and B. cereus) and fungal (A. flavus and A. parasiticus) isolates, ensuring the unique tertiary, and stereo-structure of A. terreus for penetrating the microbial cell walls and targeting the topoisomerase I. The higher dual activity of the purified CPT as antimicrobial and antitumor, emphasize their therapeutic efficiency, especially with growth of the opportunistic microorganisms due to the suppression of human immune system with the CPT uses in vivo. The putative CPT had an obvious activity against the tumor cell (MCF7) metastasis, and migration as revealed from the wound healing assay. The overall yield of A. terreus CPT was maximized with the Blackett-Burman design by twofolds increment (164.8 µg/l). The CPT yield by A. terreus was successively diminished with the multiple fungal subculturing, otherwise, the CPT productivity of A. terreus was restored, and increased over the zero culture upon coculturing with C. camphora microbiome (1.5% w/v), ensuring the restoring of CPT biosynthetic potency of A. terreus by the plant microbiome-derived chemical signals "microbial communication". This is the first report exploring the feasibility of A. terreus "endophyte of C. camphora" to be a preliminary platform for commercial production of CPT with a reliable sustainability upon uses of indigenous C. camphora microbiome.
Assuntos
Anti-Infecciosos , Cinnamomum camphora , Microbiota , Humanos , Endófitos/química , Cromatografia Líquida , Escherichia coli , Espectroscopia de Infravermelho com Transformada de Fourier , Espectrometria de Massas em Tandem , Camptotecina/farmacologia , Camptotecina/químicaRESUMO
BACKGROUND/AIM: The choice of chemotherapy agents for RAS-mutant colorectal cancer is limited, and prognosis is poor compared to RAS-wild-type colorectal cancer. The purpose of the present study was to evaluate the effectiveness of methionine restriction combined with chemotherapy in a patient with NRAS-mutant rectal cancer. PATIENTS AND METHODS: A 59-year-old female was diagnosed with lung-metastatic recurrence of NRAS-mutant rectal cancer two and a half years after resection of the primary tumor. She started chemotherapy, which consisted of fluorouracil, irinotecan (FOLFIRI), and bevacizumab, in October 2020. Eight months later, stereotactic body radiation therapy (SBRT) was performed to treat the lung metastases. She stopped chemotherapy at this point and had blood tests and computed tomography (CT) scans regularly. Her CEA level increased to 139.91 ng/ml and her lung metastasis became larger by September 2022. Therefore, she was reintroduced to FOLFIRI and bevacizumab in October 2022, and also started a low-methionine diet and oral recombinant methioninase (o-rMETase) as a supplement. RESULTS: After starting the combination therapy with o-rMETase, a low-methionine diet, FOLFIRI, and bevacizumab, blood CEA levels very rapidly decreased and were almost within the normal limits five months later. CT findings showed the lung metastasis did not grow. CONCLUSION: Methionine restriction comprising o-rMETase and a low-methionine diet combined with first-line chemotherapy was effective in a patient with NRAS-mutant rectal cancer in which metastasis had re-occurred after first-line chemotherapy alone.
Assuntos
Neoplasias Colorretais , Neoplasias Pulmonares , Neoplasias Retais , Humanos , Feminino , Pessoa de Meia-Idade , Bevacizumab , Neoplasias Colorretais/patologia , Camptotecina/uso terapêutico , Camptotecina/efeitos adversos , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/genética , Fluoruracila , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Metionina , Dieta , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Metástase Neoplásica/tratamento farmacológico , Proteínas de Membrana , GTP Fosfo-Hidrolases/genéticaRESUMO
PURPOSE: Triplet chemotherapy might be more effective than doublet chemotherapy in metastatic colorectal cancer (mCRC), but it may also be marked by increased toxicity. To investigate whether δ-tocotrienol, a vitamin E analogue, with possible neuroprotective and anti-inflammatory effects, reduces the toxicity of triplet chemotherapy, we conducted a randomized, double-blind, placebo-controlled trial in mCRC patients receiving first-line 5-fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI). MATERIAL AND METHODS: Seventy patients with mCRC were randomly assigned (1:1) to receive FOLFOXIRI plus either δ-tocotrienol or placebo at the Department of Oncology, Vejle Hospital, Denmark. Eligibility criteria were adenocarcinoma in the colon or rectum, age 18-75 years and ECOG performance status 0-1. FOLFOXIRI was given in eight cycles followed by four cycles of 5-fluorouracil. δ-tocotrienol 300 mg or placebo × 3 daily was added during chemotherapy and for a maximum of two years. The primary endpoint was time to hospitalization or death during treatment with chemotherapy. RESULTS: Median time to first hospitalization or death was 3.7 months in the placebo group (95% CI 1.93-not reached (NR)), and was NR in the δ-tocotrienol group (95% CI 1.87-NR) with a hazard ratio of 0.70 (95% CI 0.36-1.36). Grade 3-4 toxicities were uncommon in both groups, except for neutropenia, which occurred in 19 patients (58%) in the placebo group and 17 patients (50%) in the δ-tocotrienol group. There were no grade 3 or 4 peripheral sensory neuropathy. In the placebo group, 24 patients (71%) had oxaliplatin dose reductions compared to 17 patients (47%) in the δ-tocotrienol group (p = 0.047). CONCLUSION: The addition of δ-tocotrienol to FOLFOXIRI did not statistically significant prolong the time to first hospitalization or death compared to FOLFOXIRI plus placebo. Toxicity was manageable and not statistically different. There was a statistically significant difference in dose reductions of oxaliplatin pointing to a possible neuroprotective effect of δ-tocotrienol.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Tocotrienóis , Humanos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Oxaliplatina/uso terapêutico , Bevacizumab/efeitos adversos , Tocotrienóis/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina , Neoplasias do Colo/tratamento farmacológico , Fluoruracila/efeitos adversos , Neoplasias Retais/tratamento farmacológico , Leucovorina/efeitos adversosRESUMO
BACKGROUND: Previous studies have established that higher baseline quality of life (QOL) scores are associated with improved survival in patients with metastatic colorectal cancer (mCRC). We examined the relationship between overall survival (OS) and baseline QOL. PATIENTS AND METHODS: A total of 1 247 patients with mCRC participating in N9741 (comparing bolus 5-FU/LV, irinotecan [IFL] vs infusional 5-FU/leucovorin [LV]/oxaliplatin [FOLFOX] vs. irinotecan/oxaliplatin [IROX]) provided data at baseline on overall QOL using a single-item linear analogue self-assessment (LASA) 0-100 point scale. The association of OS according to clinically deficient (defined as CD-QOL, score 0-50) vs not clinically deficient (nCD-QOL, score 51-100) baseline QOL scores was tested. A multivariable analysis using Cox proportional hazards modeling was performed to adjust for the effects of multiple baseline factors. An exploratory analysis was performed evaluating OS according to baseline QOL status among patients who did or did not receive second-line therapy. RESULTS: Baseline QOL was a strong predictor of OS for the whole cohort (CD-QOL vs nCD-QOL: 11.2 months vs 18.4 months, P < .0001), and in each arm IFL 12.4 vs 15.1 months, FOLFOX 11.1 months vs 20.6 months, and IROX 8.9 months vs 18.1 months. Baseline QOL was associated with baseline performance status (PS) (P < .0001). After adjusting for PS and treatment arm, baseline QOL was still associated with OS (P = .017). CONCLUSIONS: Baseline QOL is an independent prognostic factor for OS in patients with mCRC. The demonstration that patient-assessed QOL and PS are independent prognostic indicators suggests that these assessments provide important complementary prognostic information.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Oxaliplatina/uso terapêutico , Irinotecano/uso terapêutico , Neoplasias Colorretais/patologia , Qualidade de Vida , Camptotecina , Prognóstico , Fluoruracila/uso terapêutico , Leucovorina/uso terapêuticoRESUMO
The influence of nanoparticles inside the human body and their interactions with biological macromolecules need to be explored/studied prior to specific applications. The objective of this study is to find the potential of camptothecin functionalised silver nanoparticles (CMT-AgNPs) in biomedical applications. This article primarily investigates the binding stratagem of CMT-AgNPs with calf thymus DNA (ctDNA) through a series of spectroscopic and calorimetric methods and then analyses the anticancer activity and cytotoxicity of CMT-AgNPs. The nanoparticles were synthesized using a simple one pot method and characterized using UV-Visible, fourier transform infrared (FTIR) spectroscopy, X-ray diffraction and high-resolution transmission electron microscopy (HRTEM). The average size of CMT-AgNPs is 10 ± 2 nm. A group of experimental techniques such as UV-Visible spectrophotometry, fluorescence dye displacement assay, circular dichroism (CD) and viscosity analysis unravelled the typical groove binding mode of CMT-AgNPs with ctDNA. The CD measurement evidenced the minor conformational alterations of double helical structure of ctDNA in the presence of CMT-AgNPs. The information deduced from the isothermal titration calorimetry (ITC) experiment is that the binding was exothermic and spontaneous in nature. Moreover, all the thermodynamic binding parameters were extracted from the ITC data. The binding constants obtained from UV absorption experiments, fluorescence dye displacement studies and ITC were consistently in the order of 104 Mol-1. All these results validated the formation of CMT-AgNPs-ctDNA complex and the results unambiguously confirm the typical groove binding mode of CMT-AgNPs. An exhaustive in vitro MTT assay by CMT-AgNPs and CMT against A549, HT29, HeLa and L929 cell lines revealed the capability of CMT-AgNPs as a potential anticancer agent.
Assuntos
Neoplasias Pulmonares , Nanopartículas Metálicas , Humanos , Camptotecina/farmacologia , Prata/farmacologia , Prata/química , Nanopartículas Metálicas/química , Dicroísmo Circular , Espectroscopia de Infravermelho com Transformada de Fourier , Calorimetria , DNA/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Extratos Vegetais/química , Antibacterianos/químicaRESUMO
Ophiorrhiza pumila, as a folk herb belonging to the Rubiaceae family, has become a potential source of camptothecin (CPT), which is a monoterpenoid indole alkaloid with good antitumor property. However, the camptothecin content in this herb is low, and is far from meeting the increasing clinical demand. Understanding the transcriptional regulation of camptothecin biosynthesis provides an effective strategy for improvement of camptothecin yield. Previous studies have demonstrated several transcription factors that are related to camptothecin biosynthesis, while the functions of HD-ZIP members in O. pumila have not been investigated yet. In this study, 32 OpHD-ZIP transcription factor members were genome-wide identified. Phylogenetic tree showed that these OpHD-ZIP proteins are divided into four subfamilies. Based on the transcriptome data, nine OpHD-ZIP genes were shown to be predominantly expressed in O. pumila roots, which were in line with the camptothecin biosynthetic genes. Co-expression analysis showed that OpHD-ZIP7 and OpHD-ZIP20 were potentially related to the modulation of camptothecin biosynthesis. Dual-luciferase reporter assays (Dual-LUC) showed that both OpHD-ZIP7 and OpHD-ZIP20 could activate the expression of camptothecin biosynthetic genes OpIO and OpTDC. In conclusion, this study offered the promising data for exploring the roles of OpHD-ZIP transcription factors in regulating camptothecin biosynthesis.
Assuntos
Proteínas de Transporte de Cátions , Rubiaceae , Camptotecina , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Filogenia , Proteínas de Transporte de Cátions/genética , Retículo Endoplasmático/metabolismo , Zinco/metabolismo , Rubiaceae/genéticaRESUMO
Camptothecin (CPT) and its derivatives have attracted worldwide attention because of their notable anticancer activity. However, the growing demand for CPT in the global pharmaceutical industry has caused a severe shortage of CPT-producing plant resources. In this study, phytochemical analysis of Nothapodytes tomentosa results in the isolation and identification of CPT (13: ) and 16 analogues (1: â-â12, 14: â-â17: ), including a new (1: ) and five known (9, 10, 12, 15: , and 17: ) CPT analogues with an open E-ring. In view of the potential anticancer activity of CPT analogues with an open E-ring, the fragmentation pathways and mass spectra profiles of these six CPT analogues (1, 9, 10, 12, 15: , and 17: ) are investigated, providing a reference for the rapid detection of these compounds in other plants. Furthermore, based on the fragmentation patterns of CPT (13: ) and known analogues (2: â-â8, 11, 14, 16, 18: â-â26: ), the distribution and content of these compounds in different tissues of N. tomentosa, N. nimmoniana, Camptotheca acuminata, and Ophiorrhiza japonica are further studied. Our findings not only provide an alternative plant resource for further expanding the development and utilization of CPT and its analogues, but also lay a foundation for improving the utilization of known CPT-producing plant resources.
Assuntos
Antineoplásicos Fitogênicos , Camptotheca , Magnoliopsida , Camptotecina/química , Camptotecina/metabolismo , Antineoplásicos Fitogênicos/química , Magnoliopsida/química , Camptotheca/química , Camptotheca/metabolismoRESUMO
Irinotecan (CPT-11) is an anticancer drug with indications for use in treating various cancers, but severe diarrhea develops as a side effect. We investigated the effects of green tea extract (GTE) on CPT-11-induced diarrhea, focusing on ß-glucuronidase and intestinal UGT1A1. When CPT-11 was administered to rats alone, the fecal water content was approximately 3.5-fold higher in this group than in the control group, and diarrhea developed. The fecal water content in the GTE-treated group was significantly higher than that in the control group, but the difference was smaller than that between the group treated with CPT-11 alone and the control group, and diarrhea improved. When CPT-11 was administered alone, the abundances of Bacteroides fragilis and Escherichia coli, which are ß-glucuronidase-producing bacteria, increased and interleukin-6 and interleukin-1ß mRNA levels in the colon increased, but GTE suppressed these increases. CPT-11 decreased colon UGT1A1 and short-chain fatty acid levels; however, this decrease was suppressed in the GTE-treated group. The findings that GTE decreases the abundance of ß-glucuronidase-producing bacteria and increases colon UGT1A1 levels, thereby decreasing the production of the active metabolite SN-38 in the intestinal tract, indicate that GTE ameliorates CPT-11-induced diarrhea.
Assuntos
Antineoplásicos Fitogênicos , Microbioma Gastrointestinal , Ratos , Animais , Irinotecano/efeitos adversos , Camptotecina , Antineoplásicos Fitogênicos/uso terapêutico , Diarreia/induzido quimicamente , Diarreia/tratamento farmacológico , Diarreia/prevenção & controle , Bactérias/metabolismo , Antioxidantes/uso terapêutico , Glucuronidase/genética , Glucuronidase/metabolismo , Chá/efeitos adversosRESUMO
The patient was 40s male, who underwent laparoscopic low anterior resection for his upper rectal cancer with final pathology results of tub2, pT3(SS), no lymph metastasis and fStage â ¡. He was followed up without adjuvant chemotherapy. Half a year after surgery, tumor marker was elevated and CT scan revealed multiple liver metastases. He was treated with oxaliplatin, irinotecan, Leucovorin and 5-fluorouracil(FOLFOXIRI)plus bevacizumab because of RAS mutant type. In the third courses, he has pain in the lower extremities and was diagnosed with acute lower extremity arterial occlusion. Subsequently, chemotherapy was resumed with the exception of bevacizumab, in combination with DOAC, which resulted in tumor shrinkage and allowed resection of the liver metastases.
Assuntos
Neoplasias Hepáticas , Neoplasias Retais , Masculino , Humanos , Bevacizumab , Camptotecina , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/cirurgia , Neoplasias Retais/patologia , Fluoruracila , Leucovorina , Doença Aguda , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/secundárioRESUMO
The metabolic potency of fungi as camptothecin producer elevates their prospective use as an industrial platform for commercial production, however, the loss of camptothecin productivity by fungi with the storage and subculturing are the major obstacle. Thus, screening for endophytic fungal isolates inhabiting ethnopharmacological plants with an obvious metabolic stability and sustainability for camptothecin biosynthesis could be one of the most feasible paradigms. Aspergillus terreus ON908494.1, an endophyte of Cestrum parqui was morphologically and molecularly verified, displaying the most potent camptothecin biosynthetic potency. The chemical identity of A. terreus camptothecin was confirmed from the HPLC, FTIR and LC-MS/MS analyses, gave the same molecular structure and mass fragmentation patterns of authentic one. The purified putative camptothecin displayed a strong anticancer activity towards HepG-2 and MCF-7 with IC50 values 0.96 and 1.4 µM, respectively, with no toxicity to OEC normal cells. As well as, the purified camptothecin displayed a significant antifungal activity towards fungal human pathogen Candida albicans, Aspergillus flavus, and A. parasiticus, ensuring the unique structural activity relationships of A. terreus camptothecin, as a powerful dually active anticancer and antimicrobial agent. The camptothecin productivity of A. terreus was maximized by bioprocessing with Plackett-Burman design, with an overall 1.5 folds increment (170.5 µg/L), comparing to control culture. So, the optimal medium components for maximum yield of camptothecin by A. terreus was acid why (2.0 mL/L), Diaion HP20 (2.0 g/L), Amberlite XAD (2.0 g/L), dextrin (5.0 g/L), glucose (10.0 g/L), salicylic acid (2.0 g/L), serine (4.0 g/L), cysteine (4.0 g/L) and glutamate (10.0 g/L), at pH 6 for 15 days incubation. By the 5th generation of A. terreus, the camptothecin yield was reduced by 60%, comparing to zero culture. Interestingly, the productivity of camptothecin by A. terreus has been completely restored and over increased (210 µg/L), comparing to the 3rd generation A. terreus (90 µg/L) upon addition of methanolic extracts of Citrus limonum peels, revealing the presence of some chemical signals that triggers the camptothecin biosynthetic machinery. The feasibility of complete restoring of camptothecin biosynthetic-machinery of A. terreus for stable and sustainable production of camptothecin, pave the way for using this fungal isolate as new platform for scaling-up the camptothecin production.
Assuntos
Camptotecina , Cestrum , Humanos , Camptotecina/farmacologia , Camptotecina/metabolismo , Endófitos/metabolismo , Cromatografia Líquida , Espectrometria de Massas em TandemRESUMO
Introduction: Combination therapy is a promising approach to promote the efficacy and reduce the systemic toxicity of cancer therapy. Herein, we examined the potency of a combined chemo-phototherapy approach by constructing a hyaluronidase- and reactive oxygen species-responsive hyaluronic acid nanoparticle carrying a chemotherapy drug and a photosensitizer in a tumor-bearing mouse model. We hypothesized that following decomposition, the drugs inside the nanocomplex will be released in the tumors to provide effective tumor treatment. We aimed to design a smart drug delivery system that can improve traditional chemotherapy drug delivery and enhance the therapeutic efficacy in combination with photodynamic therapy. Methods: Hydrophilic hyaluronic acid (HA) was covalently modified with a hydrophobic 5ß-cholanic acid (CA) via an ROS-cleavable thioketal (tk) linker for a targeted co-deliver of 10-Hydroxy camptothecin (HCPT) and Chlorin e6 (Ce6) into tumors to improve the efficiency of combined chemo-photodynamic therapy. Results: The obtained HA-tk-CA nanoparticle carrying HCPT and Ce6, named HTCC, accumulated in the tumor through the enhanced permeable response (EPR) effect and HA-mediated CD44 targeting after intravenous administration. Upon laser irradiation and hyaluronidase degradation, HTCC was disrupted to release HCPT and Ce6 into the tumors. Compared to the monotherapy approach, HTCC demonstrated enhanced tumor growth inhibition and minimized systemic toxicity in a tumor-bearing mouse model. Conclusion: Our results suggested that controlled dual-drug release not only improved tumor drug delivery efficacy, but also reduced systemic side effects. In addition to HCPT and Ce6 delivery, the HA-tk-CA nanocomplex can be used to deliver other drugs in synergistic cancer therapy. Since most current combined therapy uses free drugs with distinct spatiotemporal distributions, the simultaneous co-delivery of dual drugs with a remote on-demand drug delivery nanosystem provides an alternative strategy for drug delivery design.
Assuntos
Sistemas de Liberação de Medicamentos , Nanopartículas , Neoplasias , Fotoquimioterapia , Fármacos Fotossensibilizantes , Porfirinas , Animais , Camundongos , Camptotecina/química , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Ácido Hialurônico/química , Hialuronoglucosaminidase , Nanopartículas/química , Neoplasias/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Porfirinas/química , Espécies Reativas de OxigênioRESUMO
Extraction methods like maceration, ultrasonication, vortex mixer, soxhlet extraction and microwave assisted extraction (MAE), were evaluated for the extraction of Camptothecin (CPT) from the leaves and stem of Tabernaemontana alternifolia, Tabernaemontana divaricata and Tabernaemontana citrifolia. The extracts were analyzed by high performance thin layer chromatography (HPTLC). The results show that the leaves of Tabernaemontana alternifolia exhibited highest yield of CPT as compared to the other species. MAE was the most efficient extraction method with CPT extraction yield of 0.154 ± 0.004% w/w from Tabernaemontana alternifolia leaves followed by Soxhlet extraction, sonication, maceration, and vortex extraction methods.
Assuntos
Tabernaemontana , Tabernaemontana/química , Folhas de Planta/química , Camptotecina , Extratos Vegetais/químicaRESUMO
BACKGROUND: Epidermal growth factor receptor (EGFR) is a therapeutic target to which HER2/HER3 activation may contribute resistance. This Phase I/II study examined the toxicity and efficacy of high-dose pulsed AZD8931, an EGFR/HER2/HER3 inhibitor, combined with chemotherapy, in metastatic colorectal cancer (CRC). METHODS: Treatment-naive patients received 4-day pulses of AZD8931 with irinotecan/5-FU (FOLFIRI) in a Phase I/II single-arm trial. Primary endpoint for Phase I was dose limiting toxicity (DLT); for Phase II best overall response. Samples were analysed for pharmacokinetics, EGFR dimers in circulating exosomes and Comet assay quantitating DNA damage. RESULTS: Eighteen patients received FOLFIRI and AZD8931. At 160 mg bd, 1 patient experienced G3 DLT; 160 mg bd was used for cohort expansion. No grade 5 adverse events (AE) reported. Seven (39%) and 1 (6%) patients experienced grade 3 and grade 4 AEs, respectively. Of 12 patients receiving 160 mg bd, best overall response rate was 25%, median PFS and OS were 8.7 and 21.2 months, respectively. A reduction in circulating HER2/3 dimer in the two responding patients after 12 weeks treatment was observed. CONCLUSIONS: The combination of pulsed high-dose AZD8931 with FOLFIRI has acceptable toxicity. Further studies of TKI sequencing may establish a role for pulsed use of such agents rather than continuous exposure. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number: NCT01862003.
Assuntos
Neoplasias Colorretais , Receptor ErbB-3 , Humanos , Receptor ErbB-3/metabolismo , Transdução de Sinais , Quinazolinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/induzido quimicamente , Fluoruracila , Leucovorina/efeitos adversos , Camptotecina , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismoRESUMO
Multimodal collaborative therapy has been recognized as one of the more effective means to eliminate tumors in the current biomedicine research field as compared with monotherapy. Among them, by taking advantage of its high-precision and controllability, phototherapy has become a mainstay of treatment. However, physical encapsulation of free photosensitive units within nanocarriers was one of the main implementations, which might inevitably result in the photosensitizer leakage and side effect. For this purpose, a kind of multifunctional integrated polyprodrug amphiphiles, P(PFO-IG-CPT)-PEG, were prepared by reversible addition-fragmentation chain transfer polymerization from polymerizable pentadecafluorooctan monomers, indocyanine green monomers, reduction-responsive camptothecin monomers, and acid-responsive PEG based methacrylate monomers (GMA(-OH/-PEG)). The resultant copolymers could self-assemble into spherical nanoparticles in water, performing size-deformability in acidic conditions and subsequent disintegration in reduction environment as demonstrated by in vitro experiments. Furthermore, an enhanced CPT release ratio and rate from nanoparticles could be achieved by a NIR irradiation due to the hyperthermia induced by the covalently linked IG moieties. Not only that, because of the sufficient O2 content brought by PFO, the NIR light-triggered generation of 1O2 was also detected in cells. With the combination of CPT-guided chemotherapy as well as NIR light-guided photo-thermal and photodynamic therapies, fatal and irreversible damage to cancer cells was observed by cell experiments; the implanted tumor size in the mouse model was obviously shrunk upon receiving multimodal collaborative therapy. We speculate that such fabricated nanodiagnosis and treatment systems could meet the growing emergency for effective drug delivery, programmed and on-demand drug release, and multimodal integrated therapy.
Assuntos
Nanopartículas , Fotoquimioterapia , Animais , Camundongos , Fototerapia , Sistemas de Liberação de Medicamentos , Camptotecina/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Nanopartículas/uso terapêutico , Linhagem Celular TumoralRESUMO
Design of nanovectors inspired by nature is a short cut to improve the efficacy and bioavailability of chemotherapeutic agents, while reduce the toxicity. In this work, strongly hydrophobic camptothecin (CPT) was modified with different chain length of fatty acid (C4, C9 and C18) to synthesize CPT4C, CPT9C and CPT18C, respectively. CPT4C, CPT9C and CPT18C could complex with human serum albumin (HSA) readily to prepare CPT4C-HSA, CPT9C-HSA and CPT18C-HSA nanoagents. In vitro MTT assays demonstrated CPT18C-HSA possessed the highest cell killing capacity, due to the elevated cellular uptake that resulted from albumin-mediated transportation. In vivo tumor inhibition experiments verified that CPT18C-HSA had the most remarkable antitumor efficiency with distinctly lowered physiological toxicity. It could be used in large doses without obvious side effects. We believe this albumin-mediated transportation mode has great potential for efficient delivery of hydrophobic and/or physiologically unstable drugs.
Assuntos
Antineoplásicos , Camptotecina , Humanos , Camptotecina/farmacologia , Camptotecina/química , Biomimética , Ácidos Graxos , Albumina Sérica Humana , Antineoplásicos/farmacologiaRESUMO
UGT1A1 is the main enzyme that catalyzes the metabolic elimination and detoxification of SN-38, the active form of the drug irinotecan. Milk thistle products have been used widely to protect the liver from injury associated with the use of chemotherapeutic agents. To evaluate whether SN-38 metabolism can be affected by milk thistle products, the inhibitory effects of silybins on UGT1A1*1 and UGT1A1*6 were evaluated in the present investigation. Both silybin A and silybin B potently inhibited SN-38 glucuronidation catalyzed by UGT1A1*1 or UGT1A1*6. It was noteworthy that silybin A and silybin B showed synergistic effect in UGT1A1*1 microsomes at concentration around IC50, while additive effect in UGT1A1*6. According to the predicted AUCi/AUC ratios (the ratio of the area under the plasma concentration-time curve of SN-38 in the presence and absence of silybins), the coadministration of irinotecan and several milk thistle products, including silybin-phosphatidylcholine complex, two Legalon capsules, four Silymarin tablets or four Liverman capsules, may lead to clinically significant herb-drug interactions (HDI) via UGT1A1 inhibition. Meanwhile, Rgut values were much higher than 11 in all the groups, indicating potential HDI due to intestinal UGT1A1 inhibition.
Assuntos
Glucuronosiltransferase , Silybum marianum , Irinotecano/metabolismo , Silibina/metabolismo , Silibina/farmacologia , Glucuronosiltransferase/metabolismo , Microssomos Hepáticos/metabolismo , Catálise , CamptotecinaRESUMO
BACKGROUND: The efficacy of irinotecan as the adjunctive therapy to fluorouracil and leucovorin remains controversial in patients with colorectal cancer. We conduct this meta-analysis to explore the efficacy of irinotecan supplementation for colorectal cancer. METHODS: We have searched PubMed, EMBASE, Web of science, EBSCO, and Cochrane library databases through March 19, 2020, and included randomized controlled trials assessing the efficacy of irinotecan plus fluorouracil and leucovorin for colorectal cancer. RESULTS: Five randomized controlled trials were included in the meta-analysis. Compared with fluorouracil and leucovorin for colorectal cancer, irinotecan supplementation could significantly improve progression-free survival rate (hazard ratio = 0.72; 95% confidence interval [CI] = 0.58-0.90; P = .003), median progression-free survival (standard mean difference = -0.30; 95% CI = -0.44 to -0.15; P < .0001), overall survival rate (hazard ratio = 0.77; 95% CI = 0.66-0.90; P = .001), and objective response (risk ratio [RR] = 0.57; 95% CI = 0.49-0.66; P < .00001) and decrease progressive disease (RR = 2.10; 95% CI = 1.40-3.14; P = .0003), but revealed no obvious effect on complete response (RR = 0.88; 95% CI = 0.33-2.29; P = .79). The incidence of grade ≥3 adverse events in irinotecan supplementation group was increased compared to control group (RR = 0.67; 95% CI = 0.57-0.79; P < .00001). CONCLUSIONS: Irinotecan as the adjunctive therapy to fluorouracil and leucovorin can increase the survival and objective response of patients with colorectal cancer, but the incidence of grade ≥3 adverse events is found to be increased after irinotecan supplementation.