scholarly journals Novel Microcrystal Formulations of Sorafenib Facilitate a Long-Acting Antitumor Effect and Relieve Treatment Side Effects as Observed With Fundus Microcirculation Imaging

2021 ◽  
Vol 11 ◽  
Author(s):  
Junxiao Wang ◽  
Rui Liu ◽  
Yun Zhao ◽  
Zhenhu Ma ◽  
Zejie Sang ◽  
...  

The tyrosine kinase inhibitors (TKIs), including sorafenib, remain one first-line antitumor treatment strategy for advanced hepatocellular carcinoma (HCC). However, many problems exist with the current orally administered TKIs, creating a heavy medical burden and causing severe side effects. In this work, we prepared a novel microcrystalline formulation of sorafenib that not only achieved sustainable release and long action in HCC tumors but also relieved side effects, as demonstrated by fundus microcirculation imaging. The larger the size of the microcrystalline formulation of sorafenib particle, the slower the release rates of sorafenib from the tumor tissues. The microcrystalline formulation of sorafenib with the largest particle size was named as Sor-MS. One intratumor injection (once administration) of Sor-MS, but not Sor-Sol (the solution formulation of sorafenib as a control), could slow the release of sorafenib in HCC tumor tissues and in turn inhibited the in vivo proliferation of HCC or the expression of EMT/pro-survival–related factors in a long-acting manner. Moreover, compared with oral administration, one intratumor injection of Sor-MS not only facilitated a long-acting antitumor effect but also relieved side effects of sorafenib, avoiding damage to the capillary network of the eye fundus, as evidenced by fundus microcirculation imaging. Therefore, preparing sorafenib as a novel microcrystal formulation could facilitate a long-acting antitumor effect and relieve drug-related side effects.

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Lai Wei ◽  
Derek Lee ◽  
Cheuk-Ting Law ◽  
Misty Shuo Zhang ◽  
Jialing Shen ◽  
...  

Abstract Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC). However, the development of drug resistance is common. By using genome-wide CRISPR/Cas9 library screening, we identify phosphoglycerate dehydrogenase (PHGDH), the first committed enzyme in the serine synthesis pathway (SSP), as a critical driver for Sorafenib resistance. Sorafenib treatment activates SSP by inducing PHGDH expression. With RNAi knockdown and CRISPR/Cas9 knockout models, we show that inactivation of PHGDH paralyzes the SSP and reduce the production of αKG, serine, and NADPH. Concomitantly, inactivation of PHGDH elevates ROS level and induces HCC apoptosis upon Sorafenib treatment. More strikingly, treatment of PHGDH inhibitor NCT-503 works synergistically with Sorafenib to abolish HCC growth in vivo. Similar findings are also obtained in other FDA-approved tyrosine kinase inhibitors (TKIs), including Regorafenib or Lenvatinib. In summary, our results demonstrate that targeting PHGDH is an effective approach to overcome TKI drug resistance in HCC.


2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Li Liu ◽  
Jing Wang ◽  
Guifeng Sun ◽  
Qiong Wu ◽  
Ji Ma ◽  
...  

Abstract Background N6-Methyladenosine (m6A) modification has been implicated in many biological processes. It is important for the regulation of messenger RNA (mRNA) stability, splicing, and translation. However, its role in cancer has not been studied in detail. Here we investigated the biological role and underlying mechanism of m6A modification in hepatoblastoma (HB). Methods We used Reverse transcription quantitative real-time PCR (RT-qPCR) and Western blotting to determine the expression of m6A related factors. And we clarified the effects of these factors on HB cells using cell proliferation assay, colony formation, apoptotic assay. Then we investigated of methyltransferase-like 13 (METTL3) and its correlation with clinicopathological features and used xenograft experiment to check METTL3 effect in vivo. m6A-Seq was used to profiled m6A transcriptome-wide in hepatoblastoma tumor tissue and normal tissue. Finally, methylated RNA immunoprecipitation (MeRIP) assay, RNA remaining assay to perform the regulator mechanism of MEETL3 on the target CTNNB1 in HB. Results In this research, we discovered that m6A modifications are increased in hepatoblastoma, and METTL3 is the main factor involved with aberrant m6A modification. We also profiled m6A across the whole transcriptome in hepatoblastoma tumor tissues and normal tissues. Our findings suggest that m6A is highly expressed in hepatoblastoma tumors. Also, m6A is enriched not only around the stop codon, but also around the coding sequence (CDS) region. Gene ontology analysis indicates that m6A mRNA methylation contributes significantly to regulate the Wnt/β-catenin pathway. Reduced m6A methylation can lead to a decrease in expression and stability of the CTNNB1. Conclusion Overall our findings suggest enhanced m6A mRNA methylation as an oncogenic mechanism in hepatoblastoma, METTL3 is significantly up-regulated in HB and promotes HB development. And identify CTNNB1 as a regulator of METTL3 guided m6A modification in HB.


2021 ◽  
pp. 84-93
Author(s):  
A. Yu. Goryainova ◽  
A. I. Stukan ◽  
R. A. Murashko ◽  
S. V. Sharov ◽  
O. I. Kirsanova ◽  
...  

Hepatocellular carcinoma is one of the most formidable and deadly cancers. The limited possibilities of surgical methods of treatment as well as the formation of multiple drug resistance caused by the biological characteristics of both the liver tissue itself and tumor cells with their microenvironment determine the unsatisfactory indicators of relapse free survival and overall survival of patients. In addition, therapy with tyrosine kinase inhibitors, which has become the “gold” standard, has limited possibilities: a large number of side effects significantly reduce the quality of life and adherence to treatment in patients with hepatocellular cancer. The search for molecular biological targets, as well as new therapeutic agents that block these targets, does not always lead to positive results. Immunotherapy in this sense is a priority, having good tolerance, a low number of side effects, no need for additional testing of the patient’s biological material before starting treatment, high efficiency and a long response time. However, there are many unresolved questions about the duration of therapy, predicting its efficacy, the optimal combination of drugs or the use of monotherapy, the formation of priority subgroups of patients. Understanding the mechanisms of immune evasion, an ability that hepatocellular carcinoma possesses, – is the key to successful use of immunotherapeutic agents alone, in combination with tyrosine kinase inhibitors, antiangiogenic drugs or among themselves. This article provides an overview of data from clinical studies of modern drugs for the treatment of hepatocellular carcinoma and describes the mechanism of liver immunological tolerance as a possible predictive marker of sensitivity to immunotherapy. It seems promising to study the role of cells in the microenvironment of hepatocellular carcinoma for predicting the effectiveness of immunotherapy. The clinical example is used to demonstrate the successful experience of using the immunotherapeutic drug nivolumab in the treatment of hepatocellular carcinoma resistance to tyrosine kinase inhibitors. This is a classic example of duration of response to therapy, lack of reactivation of chronic viral hepatitis and controlled toxicity. All these indicators enable the clinician to consider immunotherapy as a priority option for the treatment of inoperable hepatocellular carcinoma. 


Author(s):  
A. Beliayeva ◽  
L. Garmanchuk

Cardiovascular diseases are widespread throughout the world. The incidence of diseases of the cardiovascular system has increased several times. Cardiovascular diseases have become the leading cause of death in many countries. Currently, the efforts of many researchers are aimed at studying and creating new, more effective and safe drugs and their combinations for the treatment of pathology of the cardiovascular system. Candesartan cilexetil is an angiotensin II receptor antagonist. It is used medicinally as a long-acting antihypertensive agent. However, this drug has a number of side effects. Resveratrol is a natural antioxidant. This substance exhibits pleiotropic effects, including antioxidant, anti-inflammatory, anti-aging, cardioprotective, and neuroprotective activities. The aim is investigation of acute toxicity of candesartan cilexetil and resveratrol in combination in vivo. Male and female ICR mice were used for the experiment. Animals received candesartan cilexetil and resveratrol intragastrically once. Evaluation of the effects of substances on internal organs (heart, spleen, kidneys, lungs, liver and brain) was carried out in 2 weeks after the introduction of the substances. It was shown that candesartan cilexetil with natural resveratrol did not lead to functional changes. There were no changes of behavior during the observation period. The combination of candesartan cilexetil with resveratrol did not lead to the death of mice, therefore the mean lethal dose (LD50) was not determined. The new combination of substances was safe. No side effects have been reported. The combination of candesartan cilexetil with resveratrol is non-toxic, and the use of these substances is safe for animals.


2021 ◽  
Vol 11 (8) ◽  
pp. 1347-1353
Author(s):  
Yuhui Luo ◽  
Mingyan Wang ◽  
Li Zhang ◽  
Weining Jia ◽  
Erzhe Wengu ◽  
...  

The work verified that baicalein (BCN) inhibited the appearance and progress of cervical cancer in vitro and in vivo. MTT and CCK-8 methods were used to detect the toxicity of BCN to C33A cells and the number of C33A cells, respectively. For in vivo assays, a solid tumor model of cervical cancer and ascites tumor model was successfully established. The body weight, tumor volume and weight, survival time, and ascites volume were recorded. The anti-tumor ratio and increasing rate of life span were computed. H&E staining was performed to examine the liver tissues, kidney tissues, and tumor tissues. BCN inhibits the proliferation of human cervical cancer cell line C33A and induces apoptosis. The results from in vivo assays showed that BCN suppressed tumor growth and progression with decreased tumor volume and weight in a solid tumor model. BCN significantly induced cell apoptosis in solid tumor tissues. BCN also reduced ascites volume, prolonged survival time, and increased life extension rate in the ascites tumor model. These findings indicated that BCN exerted an antitumor effect against cervical cancer both in vitro and in vivo. According to the results, BCN might act as an important antitumor agent against cervical cancer.


Pharmaceutics ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 286 ◽  
Author(s):  
Xiumei Zhang ◽  
Mingfeng Qiu ◽  
Pengcheng Guo ◽  
Yumei Lian ◽  
Enge Xu ◽  
...  

Although glucocorticoids are highly effective in treating various types of inflammation such as skin disease, rheumatic disease, and allergic disease, their application have been seriously limited for their high incidence of side effects, particularly in long term treatment. To improve efficacy and reduce side effects, we encapsulated betamethasone phosphate (BSP) into biocompatible red blood cells (RBCs) and explored its long acting-effect. BSP was loaded into rat autologous erythrocytes by hypotonic preswelling method, and the loading amount was about 2.5 mg/mL cells. In vitro, BSP loaded RBCs (BSP-RBCs) presented similar morphology, osmotic fragility to native RBCs (NRBCs). After the loading process, the loaded cells can maintain around 70% of Na+/K+-ATPase activity of natural cells. In vivo, a series of tests including survival, pharmacokinetics, and anti-inflammatory effect were carried out to examine the long-acting effect of BSP-RBCs. The results shown that the loaded cells could circulate in plasma for over nine days, the release of BSP can last for over seven days and the anti-inflammatory effect can still be observed on day 5 after injection. Totally, BSP-loaded autologous erythrocytes seem to be a promising sustained releasing delivery system with long anti-inflammatory effect.


2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Liu-Lin Xiong ◽  
Ruo-Lan Du ◽  
Jun-Jie Chen ◽  
Ya Jiang ◽  
Lu-Lu Xue ◽  
...  

Background. Colorectal cancer (CRC) is an underlying deadly malignancy with poor prognosis, lacking effective therapies currently available to improve the prognosis. C18H17NO6 (AUCAN), a kind of dibenzofuran extracted from a special plant in Yunnan Province (China), is identified as a natural anticancer agent exerting strong inhibitory activities on various cancers. Our study was committed to investigating the potency of AUCAN against colorectal cancers and further exploring the potential mechanisms via proteomic analysis. Methods. Cell Counting Kit-8 assay and immunofluorescence staining were used to investigate the effect of AUCAN on the viability and proliferation of HCT-116 cells and RKO cells. The apoptosis of HCT-116 and RKO cells after AUCAN administration was determined by the flow cytometry test. The effects of AUCAN on invasion and migration of tumor cells were investigated by the colony formation assay, wound healing test, and Transwell invasion test. Meanwhile, the energy metabolism and growth of tumor tissues after AUCAN administration with 10 mg/kg and 20 mg/kg were examined by PET-CT in vivo. The side effects of AUCAN treatment were also evaluated through blood routine and liver function examination. RKO cell proliferation and apoptosis in vivo were further determined by hematoxylin and eosin staining, TUNEL staining, and immunohistochemistry. Furthermore, the differentially expressed proteins (DEPs) involved in AUCAN treatment were determined by proteomic analysis followed by functional clustering analysis. Results. The results showed that AUCAN suppressed the migratory abilities and enhanced apoptosis of HCT-116 and RKO cell lines. Meanwhile, AUCAN treatment dramatically depressed the growth and volume of colorectal tumors in nude mice and suppressed the survival of RKO cells in tumor tissues without any side effects on the blood routine and liver function. In addition, twenty-four upregulated and forty-two downregulated proteins were identified. Additionally, functional clustering analysis concealed enriched biological processes, cellular components, molecular functions, and related pathways of these proteins involved in cellular metabolic. Finally, the protein-protein interaction analysis revealed the regulatory connection among these DEPs. Conclusions. Taken together, AUCAN exerted its significant antitumor effect without side effects in the blood routine and liver function and the underlying mechanisms were preliminarily investigated by proteomic analysis.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Charlotte E. Hinds ◽  
Bryn M. Owen ◽  
David C. D. Hope ◽  
Philip Pickford ◽  
Ben Jones ◽  
...  

AbstractGlucagon receptor agonists show promise as components of next generation metabolic syndrome pharmacotherapies. However, the biology of glucagon action is complex, controversial, and likely context dependent. As such, a better understanding of chronic glucagon receptor (GCGR) agonism is essential to identify and mitigate potential clinical side-effects. Herein we present a novel, long-acting glucagon analogue (GCG104) with high receptor-specificity and potent in vivo action. It has allowed us to make two important observations about the biology of sustained GCGR agonism. First, it causes weight loss in mice by direct receptor signalling at the level of the liver. Second, subtle changes in GCG104-sensitivity, possibly due to interindividual variation, may be sufficient to alter its effects on metabolic parameters. Together, these findings confirm the liver as a principal target for glucagon-mediated weight loss and provide new insights into the biology of glucagon analogues.


Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5038-5038 ◽  
Author(s):  
Ran Liu ◽  
Weiwei Wu ◽  
Baoan Chen ◽  
Jian Cheng ◽  
Jun Wang ◽  
...  

Abstract Multidrug resistance in cancer and adverse effects of chemotherapy are the major obstacles for cancer therapeutics. This study was aimed to investigate the efficiency of novel multifunctional Fe3O4 magnetic nanoparticles combined with chemotherapeutic agents and hyperthermia in order to reverse multidrug resistance and reduce side effects by concentrating chemotherapeutics on the target site in vivo leukemia models. K562 and K562/A02 xenograft tumor-bearing nude mice were randomly divided into 4 groups, a control group and the treatment groups were allocated to receive daunorubicin (DNR), Fe3O4 magnetic nanoparticles (Fe3O4-MNP), and Fe3O4 magnetic nanoparticles loaded with daunorubicin (DNR-Fe3O4-MNP). All groups were subjected to hyperthermia in an alternating magnetic field. Tumor volume was measured with a vernier caliper. Daunorubicin concentrations in plasma, tumor and non-tumor tissues were determined by high performance liquid chromatography (HPLC). Tumor and non-tumor tissues were stained with Hematoxylin and Eosin for histopathological and microscopic examination. Locations of Fe3O4 magnetic nanoparticles in tumor tissues were stained with Prussian blue for microscope examination. In Fe3O4-MNP and DNR-Fe3O4-MNP treated groups of both K562 and K562/A02 xenograft models, tumor temperature obviously increased and tumor volume became significantly smaller.  Apoptosis was observed in tumor cells treated with  DNR-Fe3O4-MNP groups.  In all DNR-Fe3O4-MNP groups of K562 and K562/A02 xenograft tumor models, the tumor inhibition rate, daunorubicin concentration  were higher level and  daunorubicin clearance in kidney also was delayed when compared with DNR alone treated group. Location of Fe3O4 magnetic nanoparticles with Prussian blue staining showed that Fe3O4 magnetic nanoparticles could be seen in tumor tissues. No obvious histopathological damage was observed in other non-tumor tissues.  Fe3O4 magnetic nanoparticles played an important role in increasing tumor temperature during hyperthermia, and can be delivered successfully to tumor site in an alternating magnetic field. Fe3O4 magnetic nanoparticles loaded with daunorubicin with hyperthermia had the strongest inhibitory effect on tumor and would be potential approach for improving the efficacy of chemotherapeutics, reducing side effects and reversing multidrug resistance in the treatment of leukemia. Disclosures: No relevant conflicts of interest to declare.


2021 ◽  
Author(s):  
Omer Bayazeid ◽  
Taufiq Rahman

Kinase inhibitors (KIs) represent a popular class of therapeutic agents and chemical probes but most of them tend to be polypharmacological. Receptor and non-receptor Tyrosine KIs can target more than 100 kinases simultaneously compare to other KIs. We here analyze the molecular targets of 41 U.S. Food and Drug Administration (FDA)-approved KIs. We chose 18 drugs (Tyrosine KIs) and sought out to evaluate their selectivity profile and engagement with a number of targets in vivo at clinically relevant doses . We also wanted to see whether there prevails any correlation between the target engagement profile and the reported side effects for specific KIs chosen as test cases. To explore all clinical targets of the 18 KIs, we considered the free (unbound) maximum serum concentration (Cmax) of each KI and only chose targets for which the cognate affinities lie within the reported free Cmax values, thereby allowing plausible interaction in clinical doses. We retrieved the side effects of those KIs that is reported in the FDA adverse event reporting system. We illustrate how correlation analysis of target−side effect can give a new insight into the off target of KIs and their effect on increasing the toxicity of KIs. These analyses could aid our understanding of the structural-activity relationship of KIs.


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