Efficient combination of radiotherapy and CAR-T - A systematic review.

Chimeric antigen receptor T (CAR-T) cell therapy, a groundbreaking immunotherapy. However, it faces formidable challenges in treating solid tumors, grappling with issues like poor trafficking, limited penetration, and insufficient persistence within the tumor microenvironment (TME). CAR-T cells are engineered to express receptors that target specific cancer antigens, enhancing their ability to recognize and eliminate cancer cells. This review paper explores the intricate interplay between CAR-T therapy and radiotherapy (RT), investigating their synergistic potential. Radiotherapy, a standard cancer treatment, involves using high doses of radiation to target and damage cancer cells, disrupting their ability to grow and divide. We highlight that RT modulates the TME, augments antigen presentation, and promotes immune cell infiltration, bolstering CAR-T cell-mediated tumor eradication. Molecular insights shed light on RT-induced alterations in tumor stroma, T cell recruitment promotion, and induction of immunogenic cell death. Noteworthy, strategies, such as combining hypofractionated radiotherapy with myeloid-derived suppressor cell blockade, underscore innovative approaches to enhance CAR-T cell therapy in solid tumors. Bridging indications for RT and CAR-T cells in hematological malignancies are discussed, emphasizing scenarios where RT strategically enhances CAR-T cell efficacy. The paper critically evaluates the RT as a bridge compared to traditional chemotherapy, highlighting timing and dosage considerations crucial for optimizing CAR-T therapy outcomes. In summary, the paper provides valuable insights into the intricate molecular mechanisms activated by RT and innovative strategies to improve CAR-T cell therapy, fostering a deeper understanding of their combined potential in cancer treatment.

Negative effects of cancellation during nanosecond range High-Frequency calcium based electrochemotherapy in vitro.

Drug delivery using nanosecond pulsed electric fields is a new branch of electroporation-based treatments, which potentially can substitute European standard operating procedures for electrochemotherapy. In this work, for the first time, we characterize the effects of ultra-fast repetition frequency (1-2.5 MHz) nanosecond pulses (5-9 kV/cm, 200 and 400 ns) in the context of nano-electrochemotherapy with calcium. Additionally, we investigate the feasibility of bipolar symmetric (↑200 ns + ↓200 ns) and asymmetric (↑200 ns + ↓400 ns) nanosecond protocols for calcium delivery. The effects of bipolar cancellation and the influence of interphase delay (200 ns) are overviewed. Human lung cancer cell lines A549 and H69AR were used as a model. It was shown that unipolar pulses delivered at high frequency are effective for electrochemotherapy with a significant improvement in efficiency when the delay between separate pulses is reduced. Bipolar symmetric pulses trigger the cancellation phenomenon limiting applications for drug delivery and can be compensated by the asymmetry of the pulse (↑200 ns + ↓400 ns or ↑400 ns + ↓200 ns). The results of this study can be successfully used to derive a new generation of nsPEF protocols for successful electrochemotherapy treatments.

Effects of Nanosecond Pulsed Electric Field on Immune Checkpoint Receptors in Melanoma Cells.

Checkpoint molecules such as PD-1, LAG-3, and TIM-3 are currently under extensive investigation for their roles in the attenuation of the immune response in cancer. Various methods have been applied to overcome the challenges in this field. This study investigated the effects of nanosecond pulsed electric field (nsPEF) treatment on the expression of immune checkpoint molecules in A375 and C32 melanoma cells. The researchers found that the nsPEF treatment was able to enhance membrane permeabilization and morphological changes in the cell membrane without being cytotoxic. We found that the effects of nsPEFs on melanoma included (1) the transport of vesicles from the inside to the outside of the cells, (2) cell contraction, and (3) the migration of lipids from inside the cells to their peripheries. The treatment increased the expression of PD-1 checkpoint receptors. Furthermore, we also observed potential co-localization or clustering of MHC class II and PD-1 molecules on the cell surface and the secretion of cytokines such as TNF-α and IL-6. These findings suggest that nsPEF treatment could be a viable approach to enhance the delivery of therapeutic agents to cancer cells and to modulate the tumor microenvironment to promote an antitumor immune response. Further studies are needed to explore the mechanisms underlying these effects and their impacts on the antitumor immune response, and to investigate the potential of nsPEF treatment in combination with immune checkpoint inhibitors to improve clinical outcomes for cancer patients.

TIM-3 as a promising target for cancer immunotherapy in a wide range of tumors.

T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) expression has been a trending topic in recent years due to its differential expression in a wide range of neoplasms. TIM-3 is one of the key immune checkpoint receptors that interact with GAL-9, PtdSer, HMGB1 and CEACAM1. Initially identified on the surface of T helper 1 (Th1) lymphocytes and later on cytotoxic lymphocytes (CTLs), monocytes, macrophages, natural killer cells (NKs), and dendritic cells (DCs), TIM-3 plays a key role in immunoregulation. Recently, a growing body of evidence has shown that its differential expression in various tumor types indicates a specific prognosis for cancer patients. Here, we discuss which types of cancer TIM-3 can serve as a prognostic factor and the influence of coexpressed immune checkpoint inhibitors, such as LAG-3, PD-1, and CTLA-4 on patients' outcomes. Currently, experimental medicine involving TIM-3 has significantly enhanced the anti-tumor effect and improved patient survival. In this work, we summarized clinical trials incorporating TIM-3 targeting monoclonal and bispecific antibodies in monotherapy and combination therapy and highlighted the emerging role of cell-based therapies.

Nanosecond pulsed electric field suppresses growth and reduces multi-drug resistance effect in pancreatic cancer.

Nanosecond pulsed electric fields (nsPEF) have been shown to exert anticancer effects; however, little is known about the mechanisms triggered in cancer cells by nanosecond-length pulses, especially when low, sub-permeabilization voltage is used. In this study, three human pancreatic cancer cell lines were treated with nsPEF and molecular changes at the cellular level were analyzed. Further, we assessed the efficacy of paclitaxel chemotherapy following nsPEF treatment and correlated that with the changes in the expression of multi-drug resistance (MDR) proteins. Finally, we examined the influence of nsPEF on the adhesive properties of cancer cells as well as the formation and growth of pancreatic cancer spheroids. Cell line response differed with the application of a 200 ns, 100 pulses, 8 kV/cm, 10 kHz PEF treatment. PEF treatment led to (1) the release of microvesicles (MV) in EPP85-181RDB cells, (2) electropermeabilization in EPP85-181RNOV cells and (3) cell shrinkage in EPP85-181P cells. The release of MV's in EPP85-181RDB cells reduced the membrane content of P-gp and LRP, leading to a transient increase in vulnerability of the cells towards paclitaxel. In all cell lines we observed an initial reduction in size of the cancer spheroids after the nsPEF treatment. Cell line EPP85-181RNOV exhibited a permanent reduction in the spheroid size after nsPEF. We propose a mechanism in which the surface tension of the membrane, regulated by the organization of actin fibers, modulates the response of cancer cells towards nsPEF. When a membrane's surface tension remains low, we observed some cells form protrusions and release MVs containing MDR proteins. In contrast, when cell surface tension remains high, the cell membrane is being electroporated. The latter effect may be responsible for the reduced tumor growth following nsPEF treatment.

Betulin and Its Derivatives Reduce Inflammation and COX-2 Activity in Macrophages.

Betulin is a heavily studied natural compound for its use as an anticancer or pro-regenerative agent. The structural similarity between betulin to steroids gives rise to the idea that the substance may as well act as an anti-inflammatory drug. This study is the first to describe the anti-inflammatory properties of betulinic acid, betulin, and its derivatives with amino acids 1,4-diaminebutane (Dab), 1,3-diaminepropane (Dap), Ornithine (Orn), and lysine (Lys) on murine macrophages from lymphoma site. The compounds were compared to dexamethasone. To establish the response of the macrophages to the natural compounds, we tested the viability as well as sensitivity to the inflammatory signaling (IFNγR). IL-6 secretory properties and HSP-70 content in the cells were examined. Furthermore, we characterized the effects of compounds on the inhibition of cyclooxygenase-2 (COX-2) activity both in the enzymatic assays and molecular docking studies. Then, the changes in COX-2 expression after betulin treatment were assessed. Betulin and betulinic acid are the low-cytotoxicity compounds with the highest potential to decrease inflammation via reduced IL-6 secretion. To some extent, they induce the reorganization of IFNγR with nearly no effect on COX-2 activity. Conversely, Bet-Orn and Bet-Lys are highly cytotoxic and induce the aggregation of IFNγR. Besides, Bet-Lys reduces the activity of COX-2 to a higher degree than dexamethasone. Bet-Orn is the only one to increase the HSP-70 content in the macrophages. In case of IL-6 reduction, all compounds were more potent than dexamethasone.

Celastrol and Rhynchophylline in the mitigation of simulated muscle atrophy under in vitro.

Muscular atrophy (MA) is a disease of various origins, i.e., genetic or the most common, caused by mechanical injury. So far, there is no universal therapeutic model because this disease is often progressive with numerous manifested symptoms. Moreover, there is no safe and low-risk therapy dedicated to muscle atrophy. For this reason, our research focuses on finding an alternative method using natural compounds to treat MA. This study proposes implementing natural substances such as celastrol and Rhynchophylline on the cellular level, using a simulated and controlled atrophy process. Methods: Celastrol and Rhynchophylline were used as natural compounds against simulated atrophy in C2C12 cells. Skeletal muscle C2C12 cells were stimulated for the differentiation process. Atrophic conditions were obtained by the exposure to the low concertation of doxorubicin and validated by FoxO3 and MAFbx. The protective and regenerative effect of drugs on cell proliferation was determined by the MTT assay and MT-CO1, VDAC1, and prohibitin expression. Results: The obtained results revealed that both natural substances reduced atrophic symptoms. Rhynchophylline and celastrol attenuated atrophic cells in the viability studies, morphology analysis by diameter measurements, modulated prohibitin VDAC, and MT-CO1 expression. Conclusions: The obtained results revealed that celastrol and Rhynchophylline could be effectively used as a supportive treatment in atrophy-related disorders. Thus, natural drugs seem promising for muscle regeneration.

Does the shape of the electric pulse matter in electroporation?

Electric pulses are widely used in biology, medicine, industry, and food processing. Numerous studies indicate that electroporation (EP) is a pulse-dependent process, and the electric pulse shape and duration strongly determine permeabilization efficacy. EP protocols are precisely planned in terms of the size and charge of the molecules, which will be delivered to the cell. In reversible and irreversible EP applications, rectangular or sine, polar or bipolar pulses are commonly used. The usage of pulses of the asymmetric shape is still limited to high voltage and low voltage (HV/LV) sequences in the context of gene delivery, while EP-based applications of ultra-short asymmetric pulses are just starting to emerge. This review emphasizes the importance and role of the pulse shape for membrane permeabilization by EP.

Boosting the Immune Response-Combining Local and Immune Therapy for Prostate Cancer Treatment.

Due to its slow progression and susceptibility to radical forms of treatment, low-grade PC is associated with high overall survival (OS). With the clinical progression of PC, the therapy is becoming more complex. The immunosuppressive tumor microenvironment (TME) makes PC a difficult target for most immunotherapeutics. Its general immune resistance is established by e.g., immune evasion through Treg cells, synthesis of immunosuppressive mediators, and the defective expression of surface neoantigens. The success of sipuleucel-T in clinical trials initiated several other clinical studies that specifically target the immune escape of tumors and eliminate the immunosuppressive properties of the TME. In the settings of PC treatment, this can be commonly achieved with radiation therapy (RT). In addition, focal therapies usually applied for localized PC, such as high-intensity focused ultrasound (HIFU) therapy, cryotherapy, photodynamic therapy (PDT), and irreversible electroporation (IRE) were shown to boost the anti-cancer response. Nevertheless, the present guidelines restrict their application to the context of a clinical trial or a prospective cohort study. This review explains how RT and focal therapies enhance the immune response. We also provide data supporting the combination of RT and focal treatments with immune therapies.

LAG-3 as a Potent Target for Novel Anticancer Therapies of a Wide Range of Tumors.

LAG-3 (Lymphocyte activation gene 3) protein is a checkpoint receptor that interacts with LSEC-tin, Galectin-3 and FGL1. This interaction leads to reduced production of IL-2 and IFN-γ. LAG-3 is widely expressed in different tumor types and modulates the tumor microenvironment through immunosuppressive effects. Differential expression in various tumor types influences patient prognosis, which is often associated with coexpression with immune checkpoint inhibitors, such as TIM-3, PD-1 and CTLA-4. Here, we discuss expression profiles in different tumor types. To date, many clinical trials have been conducted using LAG-3 inhibitors, which can be divided into anti-LAG-3 monoclonal antibodies, anti-LAG-3 bispecifics and soluble LAG-3-Ig fusion proteins. LAG-3 inhibitors supress T-cell proliferation and activation by disallowing for the interaction between LAG-3 to MHC-II. The process enhances anti-tumor immune response. In this paper, we will review the current state of knowledge on the structure, function and expression of LAG-3 in various types of cancer, as well as its correlation with overall prognosis, involvement in cell-based therapies and experimental medicine. We will consider the role of compounds targeting LAG-3 in clinical trials both as monotherapy and in combination, which will provide data relating to the efficacy and safety of proposed drug candidates.

Targeting CD38 in Neoplasms and Non-Cancer Diseases.

CD38 is a myeloid antigen present both on the cell membrane and in the intracellular compartment of the cell. Its occurrence is often enhanced in cancer cells, thus making it a potential target in anticancer therapy. Daratumumab and isatuximab already received FDA approval, and novel agents such as MOR202, TAK079 and TNB-738 undergo clinical trials. Also, novel therapeutics such as SAR442085 aim to outrank the older antibodies against CD38. Multiple myeloma and immunoglobulin light-chain amyloidosis may be effectively treated with anti-CD38 immunotherapy. Its role in other hematological malignancies is also important concerning both diagnostic process and potential treatment in the future. Aside from the hematological malignancies, CD38 remains a potential target in gastrointestinal, neurological and pulmonary system disorders. Due to the strong interaction of CD38 with TCR and CD16 on T cells, it may also serve as the biomarker in transplant rejection in renal transplant patients. Besides, CD38 finds its role outside oncology in systemic lupus erythematosus and collagen-induced arthritis. CD38 plays an important role in viral infections, including AIDS and COVID-19. Most of the undergoing clinical trials focus on the use of anti-CD38 antibodies in the therapy of multiple myeloma, CD19- B-cell malignancies, and NK cell lymphomas. This review focuses on targeting CD38 in cancer and non-cancerous diseases using antibodies, cell-based therapies and CD38 inhibitors. We also provide a summary of current clinical trials targeting CD38.

The role of catechin in electroporation of pancreatic cancer cells - Effects on pore formation and multidrug resistance proteins.

Catechin is a bioflavonoid known for its anti-cancer properties. In the present study, we combined theoretical and experimental approaches to reveal the potential of catechin application in the electroporation (EP) or electrochemotherapy (ECT) of pancreatic cancer cells. The molecular dynamics simulations were implemented to examine the interactions of catechin with a model of a membrane, its influence on the membrane's thickness, and the impact of the catechin-membrane interaction on the pore formation. The data were confronted with experimental measurement of the threshold electric field required for permeabilization of pancreatic cancer cells to a fluorescent dye YO-PRO-1. Further, we examined the influence of catechin on cell viability following electroporation with cisplatin or calcium ions. Finally, we investigated the catechin impact on four proteins associated with multidrug resistance: P-glycoprotein, MRP1, BCRP, and LRP. We demonstrated that catechin may boost the effects of electroporation through various mechanisms: i) increasing the cell permeability prior to electroporation ii) increasing the electroporation threshold iii) sensitization of cells to chemotherapeutic compounds. We showed that catechin incubation influences mRNA levels and mitigates the immunoreactivity of Pgp, MRP1, BCRP, and LRP but these changes did not translate to the efficacy of electrochemotherapy.

Chemotherapy and Physical Therapeutics Modulate Antigens on Cancer Cells.

Cancer cells possess specific properties, such as multidrug resistance or unlimited proliferation potential, due to the presence of specific proteins on their cell membranes. The release of proliferation-related proteins from the membrane can evoke a loss of adaptive ability in cancer cells and thus enhance the effects of anticancer therapy. The upregulation of cancer-specific membrane antigens results in a better outcome of immunotherapy. Moreover, cytotoxic T-cells may also become more effective when stimulated ex-vivo toward the anticancer response. Therefore, the modulation of membrane proteins may serve as an interesting attempt in anticancer therapy. The presence of membrane antigens relies on various physical factors such as temperature, exposure to radiation, or drugs. Therefore, changing the tumor microenvironment conditions may lead to cancer cells becoming sensitized to subsequent therapy. This paper focuses on the therapeutic approaches modulating membrane antigens and enzymes in anticancer therapy. It aims to analyze the possible methods for modulating the antigens, such as pharmacological treatment, electric field treatment, photodynamic reaction, treatment with magnetic field or X-ray radiation. Besides, an overview of the effects of chemotherapy and immunotherapy on the immunophenotype of cancer cells is presented. Finally, the authors review the clinical trials that involved the modulation of cell immunophenotype in anticancer therapy.

Contrast Media Adverse Drug Reactions in Highly Polluted Environment.

Iodinated- (ICM) and gadolinium-based (GCM) contrast media are used in radiology imaging techniques, such as computer tomography (CT) and magnetic resonance (MR), respectively. The paper aims to analyze the adverse drug reactions of ICM and GCM on different sites of the body in a highly polluted environment. We analyzed the pharmacovigilance in contrast media on the basis of reports submitted to the Regional Center for Monitoring of Adverse Drug Reactions (ADR) at the Department of Clinical Pharmacology in Wroclaw. Safety profiles were compared between different ICM and GCM and at the system organ level using the proportional reporting ratio (PRR). We analyzed 124 reports of adverse reactions related to contrast agents between 2006 and 2021. Our findings revealed that ADR combinations occurred more frequently after the use of iodinated contrast agents (72.08%) than gadolinium contrast agents (27.92%). Iomeprol and Iopromide were identified as the most frequently reported media. Each medium presented a different safety profile. Skin disorders are the most common adverse drug reactions among patients using both iodine- and gadolinium-based contrast media. Gadolinium-based contrast agents are characterized by similar organ toxicity. Conversely, iodine-based contrast agents are more diverse-some of which show tissue specificity, such as Iodixanol for the gastrointestinal system or Iohexol for the respiratory tract. This study shows relatively high occurrence of respiratory tract related ADRs in Wroclaw. We also prove that it is possible to choose the most optimal contrast agent for patients with specific organ site problems to omit the possible complications.

Prognostic and Therapeutic Role of CD15 and CD15s in Cancer.

CD15 (Lewis X/Lex) is a fucosyl (3-fucosly-N-acetyl-lactosamine) moiety found on membrane proteins of various cancer cells. These cancers include renal cancer, prostate and bladder cancers, acute leukaemias, hepatocellular carcinoma, breast cancer and melanoma. The biological role of CD15 is interaction with E-, L- and P-selectins (adhesion molecules), allowing for adhesion with endothelial cells. In this way, cancer cells start to interact with the endothelia of blood vessels and consequently move out from the blood flow to the surrounding tissues. Blockage of the antigen's function results in reduced metastatic potential. Moreover, the molecule may be a therapeutic target against cancer in monoclonal antibody-based therapies. CD15 may serve as a prognostic marker for patients and there are high hopes for its use in the immunotherapeutic treatment of tumours. CD15s is a sialyl derivative of CD15 that possesses its own unique characteristics. Its soluble form may act as a competitive inhibitor of the interaction of cancer cells with epithelial cells and thus disallow migration through the vessels. However, the prognostic relevance of CD15 and CD15s expression is very complex. This review presents a comprehensive description of the role of CD15 and CD15s in cancer development and metastasis and overviews its significance for clinical applications.

Anticancer Efficacy of 6-Gingerol with Paclitaxel against Wild Type of Human Breast Adenocarcinoma.

Breast cancer is one of the most common malignant neoplasms, and despite the dynamic development of anticancer therapies, 5-year survival in the metastatic stage is still less than 30%. 6-Gingerol (1-[4'-hydroxy-3'-methoxyphenyl]-5-hydroxy-3-decanone) is a substance contained in ginger, which exhibits anti-cancer properties. Paclitaxel is a cytostatic substance used to treat breast cancer, but its therapeutically effective dose has many adverse effects. The aim of the presented study was to assess the anticancer effect of 6-gingerol and the possibility of increasing the effectiveness of Paclitaxel in the death induction of wild type human breast cancer cells. MCF-7/WT cells were treated with drugs-6-gingerol and paclitaxel at selected concentrations. The mitochondrial activity assay, caspase 7 activity assay, ATP assay, microscopy studies, and RT-PCR assays were performed to evaluate the antitumor activity and mechanism of action of both compounds, alone and in combination. After 72 h of incubation, the mitochondrial activity showed that the combination of 5 nM Paclitaxel with 10 µM 6-Gingerol led to the same decrease in viability as the use of 20 nM Paclitaxel alone; 10 µM 6-Gingerol led to an enhancement of caspase 7 activity, with the highest activity observed after 24 h of incubation. A real-time PCR study showed that 6-Gingerol induces the simultaneous transcription of Bax with TP53 genes in large excess to BCL-2. In contrast, 5 nM Paclitaxel induces TP53 transcription in excess of BCL-2 and Bax. Our results suggest that 6-Gingerol may act as a cell death-inducing agent in cancer cells and, in combination with paclitaxel, and increase the effectiveness of conventional chemotherapy.

The Impact of COVID-19 on the Mental Well-Being of College Students.

The COVID-19 pandemic has caused an overall increase in stress and depression in society. The aim of the present research was to evaluate the psychological condition of college students during the COVID-19 pandemic and explore factors influencing their daily functioning. The study focused on four main aspects such as mental well-being, sexuality, concern about financial status, and trust in medical authorities. The study was based on a specially designed survey. The questionnaire was created using Google Forms and shared on social media sites. A total of 630 students participated in the survey, 17 surveys were excluded due to incomplete data and 613 surveys (97.30%) were considered for the final analysis. During isolation, 68.0% of students experienced fear of missing out (FOMO). A total of 73.4% were frustrated due to spending a lot of time in front of a computer. A significant decrease in motivation to study was reported by 78.1% of the respondents. Students showed significantly different attitudes towards sexuality. Concern about the financial situation was reported by 48.7% of respondents. The state of the Polish economy was of concern to 86.4% of respondents. A total of 74.5% of students declared concern about their career development. During the pandemic, 59.0% of respondents became concerned about their health. The attitude towards vaccination was described as positive by 82.5% of the respondents. The percentage of respondents experiencing negative psychological effects relative to the overall epidemiological situation of COVID-19 is troubling. Given the unexpected length and severity of the pandemic, we suggest that students' concerns be more thoroughly understood and addressed.

Molecular relation between biological stress and carcinogenesis.

This paper aims to overview different types of stress, including DNA replication stress, oxidative stress, and psychological stress. Understanding the processes that constitute a cellular response to varied types of stress lets us find differences in how normal cells and cancer cells react to the appearance of a particular kind of stressor. The revealed dissimilarities are the key for targeting new molecules and signaling pathways in anticancer treatment. For this reason, molecular mechanisms that underlay DNA replication stress, oxidative stress, and psychological stress have been studied and briefly presented to indicate biochemical points that make stressors contribute to cancer development. What is more, the viewpoint in which cancer constitutes the outcome and the cause of stress has been taken into consideration. In a described way, this paper draws attention to the problem of cancer-related post-traumatic stress disorder and proposes a novel, multidimensional oncological approach, connecting anticancer treatment with psychiatric support.

Therapeutic role of vanillin receptors in cancer.

Natural products play significant roles in the development of novel drugs. One of such compounds is vanillin - a natural substance commonly used in food. Anticancer potential of the substance is continually encouraging researchers to conduct further investigations. A rising number of publications describe the role of 4-hydroxy-3-methoxybenzaldehyde (vanillin) in the process of inhibiting tumor growth. Four vanilloid receptors play significant roles in the response of cancer cells to the natural compound. Each of these proteins can be individually affected by vanillin; thus, the substance either leads to inhibition of the cell proliferation or increases the Ca2+ level. The TRPV1, a non-selective cation channel permeable to calcium, acts on cancer development and progression. Thus, vanilloid receptors have the potential to become the target for therapeutical research. Moreover, selective inhibitors of the receptor have proved their efficacy in vitro. CK2α is an antiapoptotic, cancer-sustaining protein and, therefore, the inhibitor of apoptosis. Thus, drugs that exhibit allosteric and ATP-competitive inhibition of the protein might be crucial for cancer therapy. CAMK4 is a protein kinase expression associated with a wide array of cancers. Also, MARK4 is another kinase responsible for the stability of microtubules, overexpressed in many cancer types. Studies concerning this protein revealed that microtubule impairment might be a cancer therapy direction. This review aims to demonstrate the crucial role of described vanilloid receptors in inhibiting the proliferation of cancer cells and to prove the usefulness of using vanillin and its derivatives in the process of drug design.

Atorvastatin Modulates the Efficacy of Electroporation and Calcium Electrochemotherapy.

Electroporation is influenced by the features of the targeted cell membranes, e.g., the cholesterol content and the surface tension of the membrane. The latter is eventually affected by the organization of actin fibers. Atorvastatin is a statin known to influence both the cholesterol content and the organization of actin. This work analyzes the effects of the latter on the efficacy of electroporation of cancer cells. In addition, herein, electroporation was combined with calcium chloride (CaEP) to assess as well the effects of the statin on the efficacy of electrochemotherapy. Cholesterol-rich cell lines MDA-MB231, DU 145, and A375 underwent (1) 48 h preincubation or (2) direct treatment with 50 nM atorvastatin. We studied the impact of the statin on cholesterol and actin fiber organization and analyzed the cells' membrane permeability. The viability of cells subjected to PEF (pulsed electric field) treatments and CaEP with 5 mM CaCl2 was examined. Finally, to assess the safety of the therapy, we analyzed the N-and E-cadherin localization using confocal laser microscopy. The results of our investigation revealed that depending on the cell line, atorvastatin preincubation decreases the total cholesterol in the steroidogenic cells and induces reorganization of actin nearby the cell membrane. Under low voltage PEFs, actin reorganization is responsible for the increase in the electroporation threshold. However, when subject to high voltage PEF, the lipid composition of the cell membrane becomes the regulatory factor. Namely, preincubation with atorvastatin reduces the cytotoxic effect of low voltage pulses and enhances the cytotoxicity and cellular changes induced by high voltage pulses. The study confirms that the surface tension regulates of membrane permeability under low voltage PEF treatment. Accordingly, to reduce the unfavorable effects of preincubation with atorvastatin, electroporation of steroidogenic cells should be performed at high voltage and combined with a calcium supply.