RESUMEN

MicroRNA hsa-miR-29 was connected to a number of malignancies. Its target genes are many, among them Mcl-1 that is expressed in three possible isoforms, one of which is anti-apoptotic and another one pro-apoptotic. Ratio of these two isoforms appears to affect cell response to external stimuli. We have demonstrated that miR-29b enhanced etoposide toxicity in HeLa cell line by modulating this ratio of Mcl-1 isoforms. However, it is not known whether the described miR-29 effect is common to various cancer types or even have the opposite effect. This represents a significant problem for possible future applications. In this report, we demonstrate that miR-29b affects toxicity of 60 µM etoposide in cell lines derived from selected malignancies. The mechanism, however, differs among the cell lines tested. Hep G2 cells demonstrated similar effect of miR-29b on etoposide toxicity as was described in HeLa cells, i.e. modulation of Mcl-1 expression. Target protein down-regulated by miR-29b resulting in enhanced etoposide toxicity in Caco-2 cells was, however, Bcl-2 protein. Moreover, H9c2, Hek-293 and ARPE-19 cell lines selected as a representatives of non-malignant cells, showed no effect of miR-29b on etoposide toxicity. Our data suggest that miR-29b could be a common enhancer of etoposide toxicity in malignant cells due to its modulation of Bcl family proteins.

Asunto(s)

Etopósido , MicroARNs , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Humanos , Etopósido/toxicidad , Etopósido/farmacología , MicroARNs/genética , MicroARNs/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Células HeLa , Apoptosis/efectos de los fármacos , Apoptosis/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Células HEK293 , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/toxicidad , Células Hep G2 , Células CACO-2

RESUMEN

Paclitaxel (PTX) is a microtubule stabilizer that disrupts the normal cycle of microtubule depolymerization and repolymerization, leading to cell cycle arrest and cancer cell death. It is commonly used as a first-line chemotherapeutics for various malignancies, such as breast cancer, non-small cell lung cancer, and ovarian cancer. However, PTX chemotherapy is associated with common and serious side effects, including chemotherapy-induced peripheral neuropathy (CIPN). As cancer treatment advances and survival rates increase, the impact of CIPN on patients' quality of life has become more significant. To date, there is no effective treatment strategy for CIPN. Surtuin3 (SIRT3) is a nicotinamide adenine dinucleotide (NAD+) dependent protein deacetylase located on mitochondria. It transfers the acetyl group of the lysine side chain of acetylated substrate proteins to NAD+, producing deacetylated proteins to regulate mitochondrial energy metabolic processes. SIRT3 has been found to play an important role in various diseases, including aging, neurodegenerative diseases, cancer, heart disease, metabolic diseases, etc. However, the role of SIRT3 in CIPN is still unknown. This study found for the first time that activating SIRT3 helps to improve paclitaxel-induced CIPN. Nicotinamide riboside (NR) can protect dorsal root ganglion (DRG) mitochondria against oxidative damage caused by paclitaxel through activating SIRT3-MnSOD2 and SIRT3-Nrf2 pathway. Moreover, NR can enhance the anticancer activity of paclitaxel. Together, our research provides new strategy and candidate drug for the treatment of CIPN.

Asunto(s)

Niacinamida , Paclitaxel , Enfermedades del Sistema Nervioso Periférico , Compuestos de Piridinio , Sirtuina 3 , Paclitaxel/toxicidad , Sirtuina 3/metabolismo , Animales , Compuestos de Piridinio/farmacología , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/prevención & control , Enfermedades del Sistema Nervioso Periférico/metabolismo , Niacinamida/análogos & derivados , Niacinamida/farmacología , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/toxicidad , Ratones , Humanos , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Masculino

RESUMEN

AIMS: Paclitaxel (PTX) is extensively utilized in the management of diverse solid tumors, frequently resulting in paclitaxel-induced peripheral neuropathy (PIPN). The present study aimed to investigate sex differences in the behavioral manifestations and underlying pathogenesis of PIPN and search for clinically efficacious interventions. METHODS: Male and female C57BL/6 mice (5-6 weeks and 12 months, weighing 18-30 g) were intraperitoneally (i.p.) administered paclitaxel diluted in saline (NaCl 0.9%) at a dose of 2 mg/kg every other day for a total of 4 injections. Von Frey and hot plate tests were performed before and after administration to confirm the successful establishment of the PIPN model and also to evaluate the pain of PIPN and the analgesic effect of PD-L1. On day 14 after PTX administration, PD-L1 protein (10 ng/pc) was injected into the PIPN via the intrathecal (i.t.) route. To knock down TRPV1 in the spinal cord, adeno-associated virus 9 (AAV9)-Trpv1-RNAi (5 µL, 1 × 1013 vg/mL) was slowly injected via the i.t. route. Four weeks after AAV9 delivery, the downregulation of TRPV1 expression was verified by immunofluorescence staining and Western blotting. The levels of PD-L1, TRPV1 and CGRP were measured via Western blotting, RT-PCR, and immunofluorescence staining. The levels of TNF-α and IL-1ß were measured via RT-PCR. RESULTS: TRPV1 and CGRP protein and mRNA levels were higher in the spinal cords of control female mice than in those of control male mice. PTX-induced nociceptive behaviors in female PIPN mice were greater than those in male PIPN mice, as indicated by increased expression of TRPV1 and CGRP. The analgesic effects of PD-L1 on mechanical hyperalgesia and thermal sensitivity were significantly greater in female mice than in male mice, with calculated relative therapeutic levels increasing by approximately 2.717-fold and 2.303-fold, respectively. PD-L1 and CGRP were partly co-localized with TRPV1 in the dorsal horn of the mouse spinal cord. The analgesic effect of PD-L1 in PIPN mice was observed to be mediated through the downregulation of TRPV1 and CGRP expression following AAV9-mediated spinal cord specific decreased TRPV1 expression. CONCLUSIONS: PTX-induced nociceptive behaviors and the analgesic effect of PD-L1 in PIPN mice were sexually dimorphic, highlighting the significance of incorporating sex as a crucial biological factor in forthcoming mechanistic studies of PIPN and providing insights for potential sex-specific therapeutic approaches.

Asunto(s)

Antígeno B7-H1 , Péptido Relacionado con Gen de Calcitonina , Ratones Endogámicos C57BL , Paclitaxel , Enfermedades del Sistema Nervioso Periférico , Caracteres Sexuales , Canales Catiónicos TRPV , Animales , Paclitaxel/toxicidad , Masculino , Femenino , Ratones , Péptido Relacionado con Gen de Calcitonina/metabolismo , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Antineoplásicos Fitogénicos/toxicidad , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo

RESUMEN

Vinorelbine is a commonly used drug to treat various malignancies, such as breast cancer, non-small cell lung cancer, and metastatic pleural mesothelioma. Its side effects include severe neutropenia, local phlebitis, gastrointestinal reactions, and neurotoxicity. In view of the scarcity of research on vinorelbine's reproductive toxicity, this study evaluated the impact of vinorelbine ditartrate, a commonly used form of vinorelbine, on oocyte maturation in vitro. Our investigation revealed that vinorelbine ditartrate had no effect on oocyte meiotic resumption. However, it did reduce the rate of first polar body extrusion, suggesting that it could significantly impede the meiotic maturation of oocytes. Vinorelbine ditartrate exposure was found to disturb the regular spindle assembly and chromosome alignment, leading to the continuous activation of the spindle assembly checkpoint (SAC) and a delayed activation of the anaphase-promoting complex/cyclosome (APC/C), ultimately causing aneuploidy in oocytes. Consequently, the administration of vinorelbine is likely to result in oocyte aneuploidy, which can be helpful in providing a drug reference and fertility guidance in a clinical context.

Asunto(s)

Aneuploidia , Antineoplásicos Fitogénicos , Meiosis , Oocitos , Vinorelbina , Vinorelbina/toxicidad , Oocitos/efectos de los fármacos , Animales , Femenino , Meiosis/efectos de los fármacos , Antineoplásicos Fitogénicos/toxicidad , Ratones , Ciclosoma-Complejo Promotor de la Anafase , Huso Acromático/efectos de los fármacos

RESUMEN

Plants provide a wide array of compounds that can be explored for potential anticancer properties. Siphonochilone, a furanoterpene that represents one of the main components of the African plant Siphonochilus aethiopicus, shows numerous health benefits. However, to date, its antiproliferative properties have not been tested. The aim of this study was to analyze the cytotoxic effects of siphonochilone on a panel of cancer cell lines and its underlying mechanism of action. Our results demonstrated that siphonochilone exhibited significant cytotoxic effects on pancreatic, breast, lung, colon, and liver cancer cell lines showing a IC50 ranging from 22 to 124 µM at 72 h of treatment and highlighting its cytotoxic effect against MCF7 and PANC1 breast and pancreas cancer cell lines (22.03 and 39.03 µM, respectively). Cell death in these tumor lines was mediated by apoptosis by the mitochondrial pathway, as evidenced by siphonochilone-induced depolarization of the mitochondrial membrane potential. In addition, siphonochilone treatment involves the generation of reactive oxygen species that may contribute to apoptosis induction. In this work, we described for the first time the cytotoxic properties of siphonochilone and provided data about the molecular processes of cell death. Although future studies will be necessary, our results support the interest in this molecule in relation to their clinical application in cancer, and especially in breast and pancreatic cancer.

Asunto(s)

Apoptosis , Potencial de la Membrana Mitocondrial , Especies Reactivas de Oxígeno , Humanos , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/toxicidad , Extractos Vegetales/farmacología , Extractos Vegetales/toxicidad , Zingiber officinale/química , Supervivencia Celular/efectos de los fármacos

RESUMEN

The current study aimed to investigate the sensitivity of male testis parenchyma cells to chemotherapy agents and the protective effects and mechanisms of Morinda citrifolia (Noni) administration against structural and functional changes before and after chemotherapy (Paclitaxel (PTX)). For this purpose, rats were randomly assigned into four groups (Control = G1, PTX 5 mg/kg = G2; PTX + Noni 10 mg/kg = G3, PTX + Noni 20 mg/kg = G4). PTX was injected intraperitoneally for 4 consecutive weeks, at a dose of 5 mg/kg to all groups except the control group. Then noni was administrated in 10 (G3) and 20 (G4) mg/kg groups orally (gavage) for 14 days. Biochemical analyses, Real-Time Polymerase Chain Reaction (PCR), and immunohistochemical analyses were performed. According to our results, Total Oxidative Stress (TOS) and Malondialdehyde (MDA) were significantly increased in the PTX group (P < 0.01). Superoxide Dismutase (SOD) enzyme activity and Total Antioxidant Capacity (TAC) levels were decreased (P < 0.01). The changes in the rats treated with PTX + Noni 20 mg/kg were noteworthy. The increased levels of IL1-ß (Interleukin 1 beta) and TNFα (tumor necrosis factor-alpha) with PTX were down-regulated after treatment with PTX + Noni 20 mg/kg (P < 0.01) (9 % and 5 % respectively). In addition, Noni restored the testicular histopathological structure by reducing caspase-3 expression and significantly (61 %) suppressed oxidative DNA damage and apoptosis (by regulating the Bax (bcl-2-like protein 4)/Bcl-2 (B-cell lymphoma gene-2) ratio). In conclusion, Noni reduced cellular apoptosis and drastically changed Caspase 8 and Bax/Bcl-2 levels. Furthermore, it considerably decreases oxidative damage and can be used in testicular degeneration.

Asunto(s)

Antineoplásicos Fitogénicos , Morinda , Estrés Oxidativo , Paclitaxel , Extractos Vegetales , Testículo , Animales , Masculino , Morinda/química , Paclitaxel/toxicidad , Testículo/efectos de los fármacos , Testículo/patología , Testículo/metabolismo , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Antineoplásicos Fitogénicos/toxicidad , Antineoplásicos Fitogénicos/farmacología , Superóxido Dismutasa/metabolismo , Malondialdehído/metabolismo , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Ratas Wistar , Caspasa 3/metabolismo , Interleucina-1beta/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Proteína X Asociada a bcl-2/genética , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/genética , Sustancias Protectoras/farmacología , Ratas

RESUMEN

Vincristine-induced peripheral neuropathy is a common side effect of vincristine treatment, which is accompanied by pain and can be dose-limiting. The molecular mechanisms that underlie vincristine-induced pain are not well understood. We have established an animal model to investigate pathophysiological mechanisms of vincristine-induced pain. Our previous studies have shown that the tetrodotoxin-sensitive voltage-gated sodium channel Nav1.6 in medium-diameter dorsal root ganglion (DRG) neurons contributes to the maintenance of vincristine-induced allodynia. In this study, we investigated the effects of vincristine administration on excitability in small-diameter DRG neurons and whether the tetrodotoxin-resistant (TTX-R) Nav1.8 channels contribute to mechanical allodynia. Current-clamp recordings demonstrated that small DRG neurons become hyper-excitable following vincristine treatment, with both reduced current threshold and increased firing frequency. Using voltage-clamp recordings in small DRG neurons, we now show an increase in TTX-R current density and a -7.3 mV hyperpolarizing shift in the half-maximal potential (V1/2) of activation of Nav1.8 channels in vincristine-treated animals, which likely contributes to the hyperexcitability that we observed in these neurons. Notably, vincristine treatment did not enhance excitability of small DRG neurons from Nav1.8 knockout mice, and the development of mechanical allodynia was delayed but not abrogated in these mice. Together, our data suggest that sodium channel Nav1.8 in small DRG neurons contributes to the development of vincristine-induced mechanical allodynia.

Asunto(s)

Ganglios Espinales , Hiperalgesia , Canal de Sodio Activado por Voltaje NAV1.8 , Neuronas , Vincristina , Animales , Vincristina/toxicidad , Vincristina/farmacología , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Canal de Sodio Activado por Voltaje NAV1.8/metabolismo , Canal de Sodio Activado por Voltaje NAV1.8/genética , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Ratones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Masculino , Ratones Noqueados , Tetrodotoxina/farmacología , Potenciales de Acción/efectos de los fármacos , Ratones Endogámicos C57BL , Antineoplásicos Fitogénicos/toxicidad , Técnicas de Placa-Clamp

RESUMEN

Nanoplatform-based drug delivery plays an important role in clinical practice. Polymeric micellar (Pm) nanocarriers have been demonstrated to reduce the toxicity of paclitaxel in rats and non-small cell lung cancer (NSCLC) patients. However, the underlying toxicological profile needs to be further illustrated. Here, we used beagles as study subjects and sought to further observe the toxicological profile of polymeric micellar paclitaxel (Pm-Pac) via acute toxicity tests and short-term and long-term toxicity tests. The results from the acute toxicity test indicated that the lethal dose of Pm-Pac in beagles was 20-30 mg/kg, and the acute toxicity-targeted organs were the digestive system and immuno-haematopoietic system. The short-term toxicity test suggested that paclitaxel-induced toxicity (peripheral neuropathy toxicity, haemopoietic toxicity, heart system toxicity, and so on) in beagles can be reduced when paclitaxel is delivered via the Pm delivery system. The long-term toxicity test suggested that Pm-Pac can reduce haemopoietic toxicity in beagles. Collectively, this study provides novel insight into the toxicological profile of Pm-Pac in healthy beagles and provides a potential basis for promising clinical combination strategies in the future.

Asunto(s)

Antineoplásicos Fitogénicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Animales , Perros , Ratas , Paclitaxel/uso terapéutico , Micelas , Antineoplásicos Fitogénicos/toxicidad , Antineoplásicos Fitogénicos/uso terapéutico , Polietilenglicoles/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Polímeros/uso terapéutico , Poliésteres/uso terapéutico

RESUMEN

Chemotherapy-induced peripheral neuropathy is a challenging condition to treat, and arises due to severe, dose-limiting toxicity of chemotherapeutic drugs such as paclitaxel. This often results in debilitating sensory and motor deficits that are not effectively prevented or alleviated by existing therapeutic interventions. Recent studies have demonstrated the therapeutic effects of Meteorin, a neurotrophic factor, in reversing neuropathic pain in rodent models of peripheral nerve injury induced by physical trauma. Here, we sought to investigate the potential antinociceptive effects of recombinant mouse Meteorin (rmMeteorin) using a paclitaxel-induced peripheral neuropathy model in male and female mice. Paclitaxel treatment (4 × 4 mg/kg, i.p.) induced hind paw mechanical hypersensitivity by day 8 after treatment. Thereafter, in a reversal dosing paradigm, five repeated injections of rmMeteorin (.5 and 1.8 mg/kg s.c. respectively) administered over 9 days produced a significant and long-lasting attenuation of mechanical hypersensitivity in both sexes. Additionally, administration of rmMeteorin ( .5 and 1.8 mg/kg), initiated before and during paclitaxel treatment (prevention dosing paradigm), reduced the establishment of hind paw mechanical hypersensitivity. Repeated systemic administration of rmMeteorin in both dosing paradigms decreased histochemical signs of satellite glial cell reactivity as measured by glutamine synthetase and connexin 43 protein expression in the dorsal root ganglion. Additionally, in the prevention administration paradigm rmMeteorin had a protective effect against paclitaxel-induced loss of intraepidermal nerve fibers. Our findings indicate that rmMeteorin has a robust and sustained antinociceptive effect in the paclitaxel-induced peripheral neuropathy model and the development of recombinant human Meteorin could be a novel and effective therapeutic for chemotherapy-induced peripheral neuropathy treatment. PERSPECTIVE: Chemotherapy neuropathy is a major clinical problem that decreases quality of life for cancer patients and survivors. Our experiments demonstrate that Meteorin treatment alleviates pain-related behaviors, and signs of neurotoxicity in a mouse model of paclitaxel neuropathy.

Asunto(s)

Antineoplásicos Fitogénicos , Antineoplásicos , Neuralgia , Humanos , Ratones , Masculino , Femenino , Animales , Paclitaxel/toxicidad , Calidad de Vida , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Neuralgia/inducido químicamente , Neuralgia/tratamiento farmacológico , Antineoplásicos/efectos adversos , Analgésicos/uso terapéutico , Antineoplásicos Fitogénicos/toxicidad

RESUMEN

BACKGROUND AND PURPOSE: Opioids are commonly used for the management of cancer-associated pain and chemotherapy-induced diarrhoea. The chemotherapeutic irinotecan (CPT-11) causes severe gastrointestinal (GI) toxicity due to deconjugation of inactive metabolite SN-38 glucuronide (SN-38G) by bacterial ß-glucuronidases to the active 7-ethyl-10-hydroxycamptothecin (SN-38). Opioids are known to cause gut microbial dysbiosis, this study evaluated whether CPT-11 anti-tumour efficacy and GI toxicity are exacerbated by opioid co-administration. EXPERIMENTAL APPROACH: Eight-week-old C57BL/6 male mice were co-administration with CPT-11 ± opioid. 16S rRNA sequencing was used for gut microbiome analysis. LC-MS analyses of plasma and intestinal extracts were performed to investigate the pharmacokinetic profile of CPT-11. Histological analysis and quantitative real-time polymerase chain reaction were used to determine the severity of intestinal tissue damage. Human liver microsome In vitro assay was performed to confirm the effects of opioids on CPT-11 metabolism. KEY RESULTS: Gut microbiome analysis showed that morphine treatment induced enrichment of ß-glucuronidase-producing bacteria in the intestines of CPT-11-treated mice, resulting in SN-38 accumulation and exacerbation of GI toxicity in the small intestine. Oral administration of both antibiotics and glucuronidase inhibitor protected mice against GI toxicity induced with CPT-11 and morphine co-administration, implicating a microbiome-dependent mechanism. Additionally, morphine and loperamide decreased the plasma concentration of SN-38 and compromised CPT-11 anti-tumour efficacy, this seemed to be microbiome independent. CONCLUSION AND IMPLICATIONS: Gut microbiota play a significant role in opioid and chemotherapeutic agent drug-drug interactions. Inhibition of gut microbial glucuronidase may also prevent adverse GI effects of CPT-11 in patients on opioids.

Asunto(s)

Antineoplásicos Fitogénicos , Neoplasias , Humanos , Ratones , Masculino , Animales , Irinotecán , Analgésicos Opioides/farmacología , Disbiosis , Modelos Animales de Enfermedad , ARN Ribosómico 16S , Antineoplásicos Fitogénicos/toxicidad , Ratones Endogámicos C57BL , Camptotecina/toxicidad , Bacterias , Glucuronidasa/metabolismo , Glucuronidasa/farmacología , Derivados de la Morfina/farmacología

RESUMEN

Vincristine, an alkaloid extracted from Catharanthus rosea, is a class of chemotherapy drugs that act by altering the function of the microtubules and by inhibiting mitosis. Despite its widespread application, a major adverse effect of vincristine that limits treatment duration is the occurrence of peripheral neuropathy (PN). PN presents with several symptoms including numbness, painful sensation, tingling, and muscle weakness. Vincristine-induced PN involves impaired calcium homeostasis, an increase of reactive oxygen species (ROS), and the upregulation of tumor necrosis factor-alpha (TNF-α), and interleukin 1 beta (IL-1ß) expression. Several potential approaches to attenuate the vincristine-induced PN including the concomitant administration of chemicals with vincristine have been reported. These chemicals have a variety of pharmaceutical properties including anti-inflammation, antioxidant, and inhibition of calcium channels and calcineurin signaling pathways and increased expression of nerve growth factor (NGF). This review summarized several of these compounds and the mechanisms of action that could lead to effective options in improving vincristine-induced peripheral neuropathy (VIPN).

Asunto(s)

Antineoplásicos Fitogénicos , Antineoplásicos , Enfermedades del Sistema Nervioso Periférico , Antineoplásicos/toxicidad , Antineoplásicos Fitogénicos/toxicidad , Canales de Calcio , Humanos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/prevención & control , Vincristina/toxicidad

RESUMEN

Irinotecan, a first-line chemotherapy for gastrointestinal (GI) cancers has been causing fatal toxicities like bloody diarrhea and steatohepatitis for years. Irinotecan goes through multiple-step drug metabolism after injection and one of its intermediates 7-ethyl-10-hydroxy-camptothecin (SN-38) is responsible for irinotecan side effect. However, it is unclear what is the disposition kinetics of SN-38 in the organs subjected to toxicity. No studies ever quantified the effect of each enzyme or transporter on SN-38 distribution. In current study, we established a new physiologically based pharmacokinetic (PBPK) model to predict the disposition kinetics of irinotecan. The PBPK model was calibrated with in-house mouse pharmacokinetic data and evaluated with external datasets from the literature. We separated the contribution of each parameters in irinotecan pharmacokinetics by calculating the normalized sensitivity coefficient (NSC). The model gave robust prediction of SN-38 distribution in GI tract, the site of injury. We identified that bile excretion and UDP-glucuronosyltransferases (UGT) played more important roles than fecal excretion and renal clearance in SN-38 pharmacokinetics. Our NSC showed that the impact of enzyme and transporter on irinotecan and SN-38 pharmacokinetics evolved when time continued. Additionally, we mapped out the effect of inflammation on irinotecan metabolic pathways with PBPK modelling. We discovered that inflammation significantly increased the blood and liver exposure of irinotecan and SN-38 in the mice receiving bacterial endotoxin. Inflammation suppressed UGT, microbial metabolism but increased fecal excretion. The present PBPK model can serve as an efficacious and versatile tool to quantitively assess the risk of irinotecan toxicity.

Asunto(s)

Antineoplásicos Fitogénicos , Camptotecina , Animales , Antineoplásicos Fitogénicos/toxicidad , Camptotecina/efectos adversos , Diarrea/inducido químicamente , Glucuronosiltransferasa/metabolismo , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Irinotecán , Ratones

RESUMEN

Chemotherapy-induced neurotoxicity is a common adverse effect of cancer treatment. No medication has been shown to be effective in the prevention or treatment of chemotherapy-induced neurotoxicity. Using minoxidil as an initial template for structural modifications in conjunction with an in vitro neurite outgrowth assay, an image-based high-content screening platform, and mouse behavior models, an effective neuroprotective agent CN016 was discovered. Our results showed that CN016 could inhibit paclitaxel-induced inflammatory responses and infiltration of immune cells into sensory neurons significantly. Thus, the suppression of proinflammatory factors elucidates, in part, the mechanism of action of CN016 on alleviating paclitaxel-induced peripheral neuropathy. Based on excellent efficacy in improving behavioral functions, high safety profiles (MTD > 500 mg/kg), and a large therapeutic window (MTD/MED > 50) in mice, CN016 might have great potential to become a peripherally neuroprotective agent to prevent neurotoxicity caused by chemotherapeutics as typified by paclitaxel.

Asunto(s)

Antineoplásicos Fitogénicos , Antineoplásicos , Fármacos Neuroprotectores , Enfermedades del Sistema Nervioso Periférico , Animales , Antineoplásicos/farmacología , Antineoplásicos Fitogénicos/toxicidad , Ganglios Espinales , Ratones , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Paclitaxel/toxicidad , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/prevención & control

RESUMEN

OBJECTIVES: Colorectal cancer continues to have one of the highest incidents of occurrence with a rising rate of diagnosis among people under the age of 50. Chemotherapy with irinotecan results in severe gastrointestinal dose-limiting toxicity that is caused by the glucuronidated form of the active metabolite (SN-38G). This study evaluates herbal compounds and analogs to biomodulate the metabolism of IR to decrease dose-limiting toxicity while increasing the amount of the active metabolite. METHODS: In vitro metabolism using human liver microsomes was conducted with white willow bark (WWB) extract, select specific components of WWB, and analogues to evaluate biomodulation of the IR metabolism. Samples were analyzed using liquid chromatography-tandem mass spectrometry to measure metabolites between reactions with and without herbals components. RESULTS: WWB showed an optimal decrease (>80%) in SN-38G and a corresponding increase in SN-38 levels (128%) at a concentration of near 200 µg/mL. Tannic acid produced a 75% decrease in SN-38G with a 130% increase in SN-38 at 10 µg/mL, whereas the treatment with beta-pentagalloyl glucose and various analogues decreased SN-38G by 70% and increased SN-38 by 20% at 10 µg/mL. CONCLUSIONS: These results suggest naturally occurring compounds from WWB may have the potential to increase potency by increasing the conversion of IR to SN-38 and decrease dose-limiting toxicity of IR chemotherapy by reducing glucuronidation of SN-38.

Asunto(s)

Antineoplásicos Fitogénicos , Camptotecina , Antineoplásicos Fitogénicos/toxicidad , Camptotecina/análogos & derivados , Camptotecina/toxicidad , Glucuronatos , Glucurónidos/metabolismo , Glucurónidos/farmacología , Humanos , Irinotecán

RESUMEN

Plants of the Calea genus have been reported to contain lipophilic compounds, such as sesquiterpene lactones, with cytotoxic effect against different cancer cell lines. The aim of this manuscript was to investigate the chemical profile and cytotoxic activity of different fractions from Calea phylolepis leaves on different human cancer cell lines. The fractions were prepared using solvent extraction of increasing polarity, yielding hexane, ethyl acetate and methanolic fractions. All fractions were chemically analysed by thin layer chromatography (TLC), and their cytotoxic activity against HT-29 (colon adenocarcinoma), MCF-7 (breast cancer), U-251MG (malignant glioblastoma) and L929 (mouse fibroblast) cell lines was investigated. Among these, the hexane and ethyl acetate fractions showed higher cytotoxic effects, while the methanolic fraction did not show any cytotoxic effects. The major bioactive compound from the hexane fraction (12.15%) was isolated using chromatographic methods and was identified by nuclear magnetic resonance spectroscopy (NMR) and gas chromatography-mass spectrometry (GC-MS) analysis as 6-epi-ß-verbesinol coumarate. This compound showed activity against breast cancer cells (IC50 = 5.8 ± 1.0 µg/ml), similar to etoposide. Furthermore, 6-epi-ß-verbesinol coumarate showed low cytotoxicity to normal fibroblast cells, suggesting a high selectivity index (SI = 7.39) against breast cancer cells.

Asunto(s)

Antineoplásicos Fitogénicos/farmacología , Asteraceae/química , Neoplasias de la Mama/tratamiento farmacológico , Extractos Vegetales/farmacología , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/toxicidad , Línea Celular , Línea Celular Tumoral , Femenino , Fibroblastos/efectos de los fármacos , Cromatografía de Gases y Espectrometría de Masas , Células HT29 , Humanos , Concentración 50 Inhibidora , Células MCF-7 , Espectroscopía de Resonancia Magnética , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Extractos Vegetales/administración & dosificación , Extractos Vegetales/toxicidad , Hojas de la Planta

RESUMEN

Natural products have played a pivotal role for the discovery of anticancer drugs. Tonantzitlolones are flexibilan-type diterpenes rare in nature; therefore, few reports have shown antiviral and cytotoxic activities. This study aimed to investigate the in vivo antitumor action of Tonantzitlolone B (TNZ-B) and its toxicity. Toxicity was evaluated in mice (acute and micronucleus assays). Antitumor activity of TNZ-B (1.5 or 3 mg/kg intraperitoneally - i.p.) was assessed in Ehrlich ascites carcinoma model. Angiogenesis and reactive oxygen species (ROS) and nitric oxide (NO) production were also investigated, in addition to toxicological effects after 7-day treatment. The LD50 (lethal dose 50%) was estimated at around 25 mg/kg (i.p.), and no genotoxicity was recorded. TNZ-B reduced the Ehrlich tumor's volume and total viable cancer cell count (p < 0.001 for both). Additionally, TNZ-B reduced peritumoral microvessel density (p < 0.01), suggesting antiangiogenic action. Moreover, a decrease was observed on ROS (p < 0.05) and nitric oxide (p < 0.001) levels. No significant clinical findings were observed in the analysis of biochemical, hematological, and histological (liver and kidney) parameters. In conclusion, TNZ-B exerts antitumor and antiangiogenic effects by reducing ROS and NO levels and has weak in vivo dose-repeated toxicity. These data contribute to elucidate the antitumor action of TNZ-B and point the way for further studies with this natural compound as an anticancer drug.

Asunto(s)

Antineoplásicos Fitogénicos/farmacología , Carcinoma de Ehrlich/tratamiento farmacológico , Diterpenos/farmacología , Euphorbiaceae/química , Compuestos Macrocíclicos/farmacología , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/toxicidad , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/toxicidad , Línea Celular Tumoral , Diterpenos/administración & dosificación , Diterpenos/toxicidad , Relación Dosis-Respuesta a Droga , Femenino , Dosificación Letal Mediana , Compuestos Macrocíclicos/administración & dosificación , Compuestos Macrocíclicos/toxicidad , Ratones , Pruebas de Micronúcleos , Óxido Nítrico/metabolismo , Especies Reactivas de Oxígeno/metabolismo

RESUMEN

There has been a significant research interest in nanocrystals as a promising technology for improving the therapeutic efficacy of poorly water-soluble drugs, such as resveratrol. Little is known about the interaction of nanocrystals with biological tissue. The aim of this study was to investigate the potential use of resveratrol (RSV) and its nanocrystals (NANO-RSV) as antitumor agents in Ehrlich ascites tumour (EAT)-bearing mice and the interaction of nanocrystals with biological tissue through biochemical and histological changes of kidney, liver and EAT cells. After intraperitoneal injection of 2.5 × 106 cells into the abdominal cavity of mice, treatment of animals was started next day by injecting RSV or NANO-RSV at a dose of either 25 or 50 mg/kg every other day for 14 days. The results show that the administration of resveratrol and its nanocrystals lead to significant reductions in the proliferation of tumour cells in the abdominal cavity, and a reduction of the number of blood vessels in the peritoneum, with low systemic toxicity. In histopathological examinations, greater hepatocellular necrosis and apoptosis, hepatic fibrosis around the central vein and degeneration with minor fatty change were observed with RSV than with NANO-RSV. Inflammation with proximal tubular necrosis and renal glomerulus swelling were also observed, together with slight elevation of several biochemical parameters in both the RSV and NANO-RSV groups. In order to increase the beneficial effects and reduce risks associated with resveratrol nanocrystals, additional factors such as dose, genetic factors, health status, and the nature of the target cells should also be considered.

Asunto(s)

Antineoplásicos Fitogénicos/uso terapéutico , Nanopartículas/uso terapéutico , Resveratrol/uso terapéutico , Cavidad Abdominal/patología , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/toxicidad , Antioxidantes/farmacología , Carcinoma de Ehrlich/tratamiento farmacológico , Línea Celular , Proliferación Celular/efectos de los fármacos , Humanos , Inflamación/inducido químicamente , Inflamación/patología , Inyecciones Intraperitoneales , Masculino , Ratones , Nanopartículas/química , Nanopartículas/toxicidad , Tamaño de la Partícula , Peritoneo/irrigación sanguínea , Flujo Sanguíneo Regional/efectos de los fármacos , Resveratrol/química , Resveratrol/toxicidad , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

The chemotherapeutic agent paclitaxel (PTX) selectively binds to and stabilizes microtubule (MTs). Also, the activated formin Diaphanous Related Formin 1 (DIAPH1) binds to MTs and increases its stability. In a recent study, we found that high DIAPH1 levels correlated with increased survival of ovarian cancer (Ovca) patients. A possible explanation for this finding is that Ovca cells with high DIAPH1 levels are more sensitive to PTX. To examine this assumption, in this study the effect of DIAPH1 depletion on PTX-mediated cytotoxicity of OVCAR8 and OAW42 cells was analyzed. Our data showed that down-regulation of DIAPH1 expression decreased PTX sensitivity in both cell lines by reducing apoptosis or necrosis. Analysis of MT stability by Western blotting revealed a decreased concentration of stable, detyrosinated MTs in PTX-treated DIAPH1 knock-down compared to control cells. Also, in fixed metaphase cells the level of stable, detyrosinated spindle MTs decreased in cells with reduced DIAPH1 expression. In vitro analysis with recombinant DIAPH1 protein showed that PTX and DIAPH1 exhibited additive effects on MT-polymerization, showing that also in a cell-free system DIAPH1 increased the effect of PTX on MT-stability. Together, our data strongly indicate that DIAPH1 increases the response of Ovca cells to PTX by enhancing PTX-mediated MT-stability.

Asunto(s)

Antineoplásicos Fitogénicos/toxicidad , Apoptosis/efectos de los fármacos , Forminas/biosíntesis , Neoplasias Ováricas/metabolismo , Paclitaxel/toxicidad , Apoptosis/fisiología , Línea Celular Tumoral , Femenino , Humanos , Neoplasias Ováricas/tratamiento farmacológico

RESUMEN

Paclitaxel (PTX), which is widely used in the treatment of solid tumors, leads to dose limitation because it causes peripheral neuropathy. This study was conducted to evaluate the potential effects of hesperidin (HES), which has various biological and pharmacological properties, against PTX-induced sciatic nerve damage. For this purpose, Sprague Dawley rats were given PTX 2 mg/kg/b.w for 5 days, then 100 or 200 mg/kg/b.w HES for 10 days, and behavioral tests were conducted at the end of the experiment. The data obtained show that PTX-induced MDA, NF-κB, IL-1ß, TNF-α, COX-2, nNOS, JAK2, STAT3, and GFAP levels decreased with HES administration. Moreover, it was observed that SOD, CAT, and GPx activities inhibited by PTX increased with HES administration. It was determined that PTX caused apoptosis in the sciatic nerve by increasing Caspase-3 and Bax levels and suppressing Bcl-2 levels. HES, on the other hand, showed an anti-apoptotic effect, increasing Bcl-2 levels and decreasing Caspase-3 and Bax levels. Also, it was observed that PTX could cause endoplasmic reticulum stress (ERS) by increasing PERK, IRE1, ATF-6, GRP78 and CHOP mRNA transcript levels, while HES could alleviate ERS by suppressing them. The results indicate that neuropathic pain associated with PTX-induced peripheral neuropathy can be alleviated by HES administration and that it is a promising compound for cancer patients. In addition, it is thought that the results of the present study contain information that will shed light for researchers regarding further studies to be conducted with HES.

Asunto(s)

Antineoplásicos Fitogénicos/toxicidad , Hesperidina/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Paclitaxel/toxicidad , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/prevención & control , Animales , Relación Dosis-Respuesta a Droga , Masculino , Enfermedades del Sistema Nervioso Periférico/metabolismo , Ratas , Ratas Sprague-Dawley

RESUMEN

Sesuvium sesuvioides(Fenzl) Verdc. (Aizoaceae) is commonly known as BarriUlwaiti and used in folklore remedies; i.e. arthritis, gout, epistaxis, hemorrhage, smallpox, chickenpox, cold and flu by the local practitioners in the Cholistan desert. In the current study, fresh and dried plant material was examined macroscopically and microscopically. Transverse sections of plant parts such as leaf, stem, root and flower were also examined. Physico-chemical and fluorescence analysis according to WHO recommendations for standardization of plant material were performed. Phytochemical screening maybe helpful in determining the secondary metabolites responsible for their biological activities. Mineral analysis (Na+, K+, Li+, Ca2+, Mg2+, Cl-, Zn2+, Cu2+ and Fe2+), total fat and crude proteins were estimated to evaluate the nutritional value of the plant. In in-vitro cytotoxic activity, n-hexane fraction (50µg) showed significant results against Human T-lymphoblastic Leukemia CCRF-CEM cell lines followed by methanol and chloroform fractions. This study will be worthwhile for the correct identification and for observing any type of adulteration. This observation will be helpful for differentiating this species from closely related species of the same genus or family.

Asunto(s)

Aizoaceae/química , Antineoplásicos Fitogénicos/farmacología , Supervivencia Celular/efectos de los fármacos , Fitoterapia , Extractos Vegetales/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/toxicidad , Línea Celular Tumoral , Humanos , Medicina Tradicional , Fitoquímicos , Componentes Aéreos de las Plantas/química , Extractos Vegetales/química , Extractos Vegetales/toxicidad