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  • Open access
  • 112 Reads
Photosensitizer chlorophyllin in the treatment of oncopathologies

The antitumor effect of photodynamic therapy (PDT) consists of a combination of direct toxic damage to tumor cells with indirect mechanisms of suppression of tumor vascularization and activation of the immune response. The combination of a photosensitizer (PS) and light in the presence of oxygen leads not only to selective tissue destruction, but also to long-term control over the first cell proliferation. The presence and severity of the above elements of selective destruction largely depends on the properties of the PS. One of the most important directions for increasing the efficiency of PDT is the synthesis of PSs with increased selectivity of accumulation in the pathological site. It has been shown that PSs of the chlorin series have similar selectivity for target cells, low toxicity, and good photophysical properties. Currently, the drug Photoditazin is used for PDT for oncological diseases. Chlorophyll (phytolesterified magnesium porphyrin) is similar in action to bilirubin, which is a candidate molecule responsible for the body's antioxidant defenses.

In this study, it was shown that chlorophyllin is able to accumulate in pathological tissues and influence to the P450 cytochrome. The prooxidative and antiproliferative effects of chlorophyllin as a component of a drug «OXYChlorophyll» was studied in the models «in vitro» and «in vivo». Chlorophyllin provides good absorption, digestibility, stability and accurate transport to target cells. It has been shown to produce antiproliferative effects in Ehrlich's ascites carcinoma (EAC) to the cell line in a dose-dependent manner. Chlorophyllin have been observed to increase the production of reactive oxygen species (ROS) and enzymatic activity of EAC cells, including the production of mitochondrial/whole-cell ROS, and alter the ratio of reduced-to-oxidized glutathione. Importantly that «Chlorophyll OXY»-mediated suppression of EAC cell viability has been replicated in «in vivo» experiments, where its administration a resulted in the reduction of tumor size in mice. In conclusion, this data suggests that chlorophyllin mediated changes on the redox status of cancer cells leads to a decrease in its proliferation.

Funding: The reported study was funded by RFBR, project number 20-33-90185.

  • Open access
  • 111 Reads
Cytotoxic activity of gallic acid and myricetin against ovarian cancer cells by production of reactive oxygen species.

Some studies demonstrate that gallic acid (GA) and myricetin (MYR) isolated from Rhus trilobata provide the therapeutic activity of the plant against cancer. However, few reports demonstrate that both compounds also could have therapeutic potential in ovarian cancer treatment. Therefore, to evaluate the cytotoxic activity of GA and MYR against ovarian cancer cells and to determine the possible action mechanism present is important. With this purpose, SKOV-3 ovarian adenocarcinoma cells (HTB-77™, ATCC®) were cultivated at 37°C with 5% CO2 according to supplier's instructions for determine the biological activity of GA and MYR by confocal/transmission electron microscopy, PI-flow cytometry, H2DCF-DA, MTT and Annexin V/PI assays. Possible molecular targets of the compounds were determined by Similarity Ensemble Approach model. Results showed that GA and Myr treatments decreased viability of SKOV-3 cells at 50 and 166 μg/mL respectively (p ≤ 0.05, ANOVA vs vehicle group); As well as morphological changed (cytoplasmatic reduction, nuclear chromatin condensation, cytoplasmic vesicles increment, polymerized actin, and stabilized tubulin), cell cycle arrest (GA: 8.3% G2/M and MYR: 78% G1), and apoptosis induction (GA: 18.9% and MYR: 8.1%), because to ROS generation (34 to 42%) for 24 h (p ≤ 0.05, ANOVA vs vehicle group). In silico studies demonstrated that GA and MYR interact with carbonic anhydrase and PI3K, respectively. As conclusions, GA and MYR show cytotoxic activity against SKOV-3 cells through ROS production, which modify the cytoskeleton and induce apoptosis mainly. Therefore, GA and Myr could be considered as a starting point for the development of novel anticancer agents.

  • Open access
  • 113 Reads
Machine learning for gene expression-based prediction of individual drug response for cancer patients


Various machine learning (ML) methods are applied for prediction of individual clinical efficiency of cancer drugs and therapeutic regimens. As features for ML, different multi-omics data may be used, such as genomic, transcriptomic, proteomic, and interactomic (activation levels of intracellular molecular pathways) profiles.


We proposed a next-generation ML approach termed FloWPS (FLOating-Window Projective Separator) that uses pre-processing/trimming/filtration of multi-omics features when building the ML models, in order to preclude extrapolation in the feature space. Additionally, FloWPS allows to neglect the influence of preceding cases from the training dataset, which are too distant in the feature space from the case that must be classified. Such extrapolation, as well as too distant instances, can cause model overtraining and results in decreased ML accuracy.


Using Gene Expression Omnibus (GEO), The Cancer Genome Archive (TCGA), and Tumor Alterations Relevant for GEnomics-driven Therapy (TARGET) project databases we selected 27 gene expression datasets for cancer patients, annotated with clinical response status. Each dataset had the same cancer type and treatment regimen. The biggest dataset included 235, and the smallest - only 41 patient cases. To form the robust set of marker features (gene expression levels), we applied the leave-one-out (LOO) cross-validation test that selected genes with the highest AUC values for good-vs-poor responder discrimination.

When using the blind/agnostic LOO approach for data trimming, we demonstrated essential improvement of ML quality metrics (AUC, sensitivity and specificity) for FloWPS-based clinical response classifiers for all global ML methods applied, such as support vector machines (SVM), random forest (RF), binomial naïve Bayes (BNB), adaptive boosting (ADA), as well as multi-level perceptron (MLP). Namely, the AUC for the treatment response classifiers increased from 0.61–0.88 range to 0.70–0.97.


To exclude possible overtraining effects of data trimming, we evaluated the relative importance of gene expression features for ML models. Our results showed that pre-processing significantly increases the correlation of feature importance metrics among different ML methods. Since different ML methods produce different geometrical models of class separation in the features space, such increase of correlation indicates that FloWPS unveils essential features rather than adapts to random noise, and thus increases the classifier accuracy.


Considering our ML trial with 27 clinically annotated cancer gene expression datasets, the BNB method showed best performance for data trimming and was the most effective for classifying the clinical response using multi-omics features, with minimal, median and maximal AUC values equal to 0.77, 0.86 and 0.97, respectively.

  • Open access
  • 90 Reads
Covalently Cross-linked Particles based on Arabinoxylans: Antioxidant Activity and Cytotoxicity on a Human Colon Cell Line

Polysaccharide-based carriers have become attractive materials for the delivery of therapeutics targeted to colon. Ferulated arabinoxylans (AX), polysaccharides with gelling and antioxidant capacities that can be degraded by colonic microbiota are ideal candidates for use as oral drug delivery systems. Recently, AX-based microspheres have demonstrated potential applications as colon-targeted drug carriers. The non-cytotoxicity of AX-based microspheres is a required property for their use as a colon-targeted biomaterial. This study reports the antioxidant activity and cytotoxicity on human colon cells of covalently cross-linked particles based on AX (AXP). The in vitro antioxidant activity of AX before and after gelation was measured using the ABTS+, DPPH, and FRAP methods. Besides, the effect of AX and AXP on the proliferation of human colon cells (CCD 841 CoN) was evaluated using the MTT assay. AXP presented a spherical shape and rough surface with a three-dimensional and porous network. Gelation decreased the antioxidant activity of AX by 61–64 %. AX and AXP did not affect proliferation or show any toxic effect on the regular human colon cell line CCD 841 CoN. The results indicate that AXP are promising biocompatible materials with antioxidant activity. AXP could be suitable materials for the development of drug delivery systems targeted to colon.

  • Open access
  • 74 Reads
Ramucirumab as a second-line treatment for locally advanced or metastatic urothelial carcinoma: a meta-analysis of randomized clinical trials

Improvement of treatment outcomes in patients with locally advanced or metastatic urothelial carcinoma represents an important unmet need, since survival remains poor in patients who progressed after first-line treatment. The purpose of this study was to investigate the effects of ramucirumab, a human monoclonal antibody which binds to VEGFR-2, in the treatment of locally advanced or metastatic urothelial carcinoma. A literature search of PubMed and CENTRAL was conducted. Outcomes of interest were overall survival (OS), progression-free survival (PFS) and rate of adverse events. Time-to-event outcomes were combined using the generic inverse-variance method and presented as hazard ratio (HR) with 95% confidence intervals (95%CI), while dichotomous events were combined using the Mantel-Haenszel method and presented as odds ratio (OR) with 95%CI. All analyses were performed in RevMan 5.3. Literature search identified two randomized controlled trials. Addition of ramucirumab to docetaxel resulted in a statistically significant improvement in PFS (HR=0.55, 95%CI 0.31-0.96, p=0.030), while the difference was not significant for OS (HR=0.86, 95%CI 0.71-1.04, p=0.12). Subgroup analysis by sex, age (<65 and ≥65 years), baseline hemoglobin (<10 g/dL and ≥10 g/dL), presence of visceral metastases and presence of liver metastases did not identify a subgroup in which improvement in OS was present. The difference in treatment-related grade≥3 adverse events was not significant (OR=1.47, 95%CI 0.95-2.27, p=0.08). Ramucirumab in addition to docetaxel significantly improved PFS in patients with locally advanced or metastatic urothelial carcinoma. Future studies are necessary to identify a subset of patients who might have a significant improvement in OS.

  • Open access
  • 112 Reads
Synergistic effects of 5-fluorouracil in combination with diosmetin in colorectal cancer cells

Background:Colorectal cancer (CRC) is among the most common occurring cancer. The management of CRC includes laparoscopic surgery, radiotherapy, chemotherapies and neoadjuvant. However, the conventional chemotherapies have poor impact on combating CRC and are associated with sever toxic effects and high relapse. Therefore, searching for a new combination regimen is a favorable consideration. Objective:The aim of this study was to elucidate the synergistic effect of 5-fluorouracil (5-FU) and diosmetin in an in vitromodel in colorectal cancer cell. Methodology:MTT assay was conducted on HCT-116 cancer cells and treated with concentration gradient of 5-FU and diosmetinindividually and in combination. Combination index (CI) and dose reduction index (DRI) were calculated using Compusyn software.Isobologram analysis and synergism determination was done via Combenefit software tool and synergy score was calculated using SynergyFinder 2.0 software tool. Apoptotic features of cells were determined via AO/PI double staining assay and Annexin V assay using fluorescent microscope and flow cytometry technique, respectively. Results:findings showed that the DRI of 5-FU was 5 folds lower in the combination treatment with an CI value less than one, which indicates the synergistic effect. AO/PI microscopic results revealed signs of apoptosis and dead cells after 72 h of treatment. Flow cytometry analysis confirmed the apoptotic effects of combination was more prominent as compared to 5-FU alone.

Conclusion:The findings of this study offered a potential strategy to reduce the cytotoxicity and enhance the efficacy of 5-FU on colorectal cancer cells through a synergistic study model.

  • Open access
  • 78 Reads
In vitro characterization of an anti-HER2 affibody-monomethyl auristatin E conjugate in HER2-positive breast cancer cells

Antibody-drug conjugates (ADCs) are used in anticancer therapy with some limitations due to their molecular properties. An alternative to monoclonal antibodies is the affibody, composed of 58 aminoacids, with lower binding affinities, small size, and rapid blood clearance and tissue distribution. We investigated the in vitro efficacy of a novel anti-HER2 ZHER2:2891 affibody conjugated to a cytotoxic drug auristatin E (MMAE) in HER2-positive human cancer cells. Adenocarcinoma cell line SK-BR-3, expressing high levels of HER2, and mammary gland adenocarcinoma MDA-MB-231, expressing basal levels of HER2, were treated with ZHER2:2891DCS-MMAE and trastuzumab (as reference compound).

ZHER2:2891DCS-MMAE induced a significant time-dependent toxic effect in SK-BR-3 cells. A 30% reduction in cell viability was found after 10 min exposure at 7 nM with an IC50 of 80.2 nM. On the contrary, MDA-MB-231 cells were not affected by the affibody complex. The HER2-specific cytotoxic effect of the ZHER2:2891DCS-MMAE has been also confirmed by measuring apoptosis by flow cytometry. In SK-BR-3 cells, increasing concentrations of conjugated affibody, induced cell death after 10 min of treatment with the strongest effect observed after 48 hours. Also, treatment with ZHER2:2891DCS-MMAE reduced (up to 50%) HER2 expression at both mRNA and protein levels in SK-BR-3 cells after 24 hours of treatment.

In conclusion, the cytotoxic conjugate based on the anti-HER2 affibody and MMAE efficiently interacts with HER2 over-expressing cancer cells, allowing the selective and specific delivery of the cytotoxic payload. The basal HER2 expressing cells are not affected most probably due to a lower uptake of drug conjugate. This confirms that affibody may be used to target HER2 overexpressing cells while sparing normal cells.

  • Open access
  • 146 Reads
A green method to synthesis the size-controllable gold nanostars for photo-based therapies

Photothermal therapy (PTT) is a novel therapy in the treatment of cancer which bases on the conversion of photon energy into heat (>43oC), and photoacoustic imaging (PAI) is a novel imaging technique for cancer diagnostic and therapeutic monitoring. To enhance the treatment depth of PTT and the signal of PAI, the near-infrared (NIR)-absorbing photothermal agents have been used. The development of NIR-absorbing photothermal agents with excellent properties such as highly photothermal stability, high absorption in the NIR region, and excellent biocompatibility is needed in modern biomedicine. Gold nanostar (AuNS) has potential applications in the biomedical field owing to the large NIR absorption and the high NIR photothermal effect. However, the reported methods to synthesis AuNS are complicated and toxic, which is a serious issue for its practice. In this work, a novel green synthesis procedure using chitosan polymer from marine and vitamin C for the preparation of AuNS was introduced. Chitosan was used as a stabilizer, shape-directing, and size-controllable agent for the preparation of AuNS for the first time. The obtained AuNS sized from 111 to 225 nm with different absorption peaks. The AuNS exhibited NIR absorption with excellent biocompatibility toward non-cancerous and cancerous cell lines. The in vitro tests proved the high efficiency of obtained AuNS on both PTT and PAI.

  • Open access
  • 78 Reads
Development of photothermal membrane for treatment of infected wound: A proof-of-concept

Wound infection is a serious issue because of multi-drug resistance bacteria, thus developing an advanced therapy is a needed demand. Photothermal therapy (PTT) is a novel noninvasive strategy that utilizes PTT agents to convert near-infrared (NIR) light energy into heat to kill living cells. In this work, we developed the PTT agent containing membrane to treat the wound infection for the first time. Palladium nanoparticles (PdNPs) were chosen as PTT agents owing to their high stability, good biocompatibility, excellent photothermal property, and simple-green preparation. Chitosan (CS) has been widely studied in tissue engineering due to its good properties such as biocompatible, biodegradable, antibacterial, and wound-healing abilities. However, the poor workability and high brittleness of CS limit the applications of CS in tissue engineering. Thus, we combined polyvinyl alcohol (PVA) and CS to have the membrane with high flexibility, wettability, highly porosity. The test on cells showed that the membrane has high biocompatibility. The combination of PdNPs loading CS/PVA membrane and laser irradiation killed most of the bacteria in vitro.

  • Open access
  • 183 Reads
Multi-Omics-Driven Biomarkers for Precision Medicine in Cutaneous Melanoma

Cutaneous melanoma (CM) is a public health issue and a major challenge for scientists. At the dawn of the "omics era", we witnessed groundbreaking advances in CM molecular stratification and therapeutic management assisted by genomic profiling and sequencing technologies. However, melanomagenesis is a complex and multifactorial process that cannot be restricted only to genomic aspects, requiring investigation from a multi-omics perspective. The integration of multi-omics data in a physiological and clinical context may provide new clues about the mechanisms of CM initiation, progression, and metastasis, as well as novel biological pathways amenable to targeted therapy. The Cancer Genome Atlas (TCGA) is an important repository of multiple types of omics data, and in particular, for CM, it has been shown that multi-integration can lead to prognosis models with improved prediction performance. Among clinicians and researchers, multi-omics-based-biomarkers are regarded with enthusiasm as they offer new opportunities for clinical trials design and reduce the time and cost of developing new treatments. We present herein how droplet digital PCR (ddPCR), a relatively young omics technology can complement existing approaches in the field to detect multiple types of alterations in both body fluids as well as formalin-fixed tissues harvested from CM patients and how these findings may broaden our vision on CM research, diagnosis, prognosis and therapy in the context of precision medicine.

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