Efficacy Of Chemotherapeutic Agents Research Articles

Pharmacokinetics and safety of topical fluralaner in koalas (Phascolarctos cinereus)

Sarcoptic mange (etiological agent Sarcoptes scabiei) is among the most important parasitic diseases of some marsupial species and has been an emerging disease of koalas, causing welfare and conservation implications. Fluralaner (Bravecto® MSD Animal Health), an ectoparasiticide of the isoxazoline class, has been demonstrated as a long-lasting and efficacious chemotherapeutic agent against sarcoptic mange in multiple mammal species and may also be beneficial for impacted koalas. Here, we evaluated the pharmacokinetics and clinical safety of fluralaner in koalas. Healthy captive individuals were treated topically with 85 mg/kg fluralaner administered to the interscapular epidermis. Following treatment, fluralaner was detected in plasma using ultra-performance liquid chromatography and tandem mass-spectrometry over a 12-week period. The mean maximum plasma concentration (Cmax) was 66.4 ng/mL; mean time was Cmax of 2.71 days; plasma elimination half-life (T1/2) was 30.91 days; and mean residence time (MRT) was 27.38 days. Haematological, blood biochemical, animal husbandry and clinical observations, over the same time period, demonstrated fluralaner was well tolerated. Overall, this research suggests fluralaner is a safe and long-lasting chemotherapeutic agent that may be efficacious against S. scabiei in koalas. Further research focussed on quantifying efficacy in captive and field settings, and across a range of disease severities would be valuable.

Docetaxal induced scleroderma like disease

Scleroderma like skin disease is a rare entity among the drug induced dermatological manifestations. It is attributed to various drugs and recently to certain oncological medications especially taxanes. Despite being an efficacious chemotherapeutic agent, it results in scleroderma like skin lesions rarely it resolves in some patients if detected early with omission of the culprit drug with or without steroids. Despite its rarity in literature untreated cases develop severe functional limitation due to skin fibrosis. After an exploration of literature search herein we report the first case of docetaxal induced scleroderma in a Sri Lankan which was detected and promptly treated with steroids successfully. We report this case to make clinicians aware about this condition when encountered with a patient having skin fibrosis with background history of chemotherapy, the possibility of a drug induced scleroderma.

Abstract 1750: Removal of mucin glycans by Bifidobacterium bifidum enhances chemotherapy-mediated cell death in mucinous adenocarcinomas

Abstract Background: Mucinous colorectal adenocarcinoma, a subtype of colorectal cancer, is characterized by mucin production and increased resistance to several chemotherapeutic interventions; resulting in a poorer prognosis compared to non-mucus secreting cancers. Advances in treatment are stymied by the limited number of efficacious chemotherapeutic agents. The most common drug used to treat colorectal cancer is 5-Fluorouracil (5-FU), but less than 10% of mucinous tumors respond to this drug. The production of mucus has been theorized to limit the uptake of chemotherapeutic agents via charge repulsion and size exclusion, thereby promoting chemo-resistance and driving poor outcomes. Hypothesis: We predict that mucin-degrading microbes secrete glycosyl hydrolase enzymes which cleave mucin glycans and promote the uptake of chemotherapeutic agents and enhance cell death. Methods & Results: We queried the human gut microbiota and identified multiple diverse microbes which encode enzymes to degrade mucin glycans. Among the mucin-degrading bacteria, we found that Bifidobacterium bifidum harbored one of the most extensive repertoires of mucin-degrading enzymes. B. bifidum was grown in a chemically defined medium with or without porcine intestinal mucus and the secreted products were then added to mucus-producing adenocarcinoma cell lines: HT29-MTX and T84 cells. Supernatant from cultures with mucus removed sialic acid residues and enhanced 5-FU uptake after 48 hrs in both cell lines. Supernatant without mucus also promoted 5-FU mediated cell death; although to a lesser degree than supernatant from cultures incubated with mucus. Gene expression analysis and immunostaining revealed decreased MUC13 gene expression and protein in B. bifidum metabolite treated cell lines compared to media controls. In contrast, we found that secreted products from B. dentium, which is unable to degrade mucus, had no effect on 5-FU induced cell death. Conclusions: Our data suggests that B. bifidum elicits chemo-sensitivity via the production of mucin-degrading enzymes, which cleave negatively charged sialic acid, increasing the activity of 5-FU in these cancers as well as by lowering the expression of adherent mucins. This work points to a novel role of mucin-degrading microbes to promote 5-FU penetration of mucinous colorectal adenocarcinoma. This strategy has the potential to provide unique treatment strategies for patients with mucinous colorectal cancer. Citation Format: Leah K. Stripe, Amy C. Engevik, Mindy A. Engevik. Removal of mucin glycans by Bifidobacterium bifidum enhances chemotherapy-mediated cell death in mucinous adenocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1750.

Acetophenone protection against cisplatin-induced end-organ damage

Cisplatin is a widely used and efficacious chemotherapeutic agent for treating solid tumors, yet it causes systemic end-organ damage that is often irreversible and detrimental to quality of life. This includes severe sensorineural hearing loss, hepatotoxicity, and renal injury. Based on the hard-soft acid-base theory, we recently developed two acetophenone-derived, enol-based compounds that directly interfere with the side effects of cisplatin. We investigated organ-specific and generalized toxicity in order to define dose-dependent responses in rodents injected with cisplatin with or without the protective compounds. All metrics that were used as indicators of toxicity showed retention of baseline or control measurements when animals were pre-treated with acetophenones prior to cisplatin administration, while animals injected with no protective compounds showed expected elevations in toxicity measurements or depressions in measurements of organ function. These data support the further investigation of novel acetophenone compounds for the prevention of cisplatin-induced end-organ toxicity.

Pharmacological manipulation of Ezh2 with salvianolic acid B results in tumor vascular normalization and synergizes with cisplatin and T cell-mediated immunotherapy

Tumor vasculature is characterized by aberrant structure and function, resulting in immune suppressive profiles of tumor microenvironment (TME) through limiting immune cell infiltration into tumors. The defective vascular perfusion in tumors also impairs the delivery and efficacy of chemotherapeutic agents. Targeting abnormal tumor blood vessels has emerged as an effective therapeutic strategy to improve the outcome of chemotherapy and immunotherapy. In this study, we demonstrated that Salvianolic acid B (SalB), one of the major ingredients of Salvia miltiorriza elicited vascular normalization in the mouse models of breast cancer, contributing to improved delivery and response of chemotherapeutic agent cisplatin as well as attenuated metastasis. Moreover, SalB in combination with anti-PD-L1 blockade retarded tumor growth, which was mainly due to elevated infiltration of immune effector cells and boosted delivery of anti-PD-L1 into tumors. Mechanistically, tumor cell enhancer of zeste homolog 2 (Ezh2)-driven cytokines disrupted the endothelial junctions with diminished VE-cadherin expression, which could be rescued in the presence of SalB. The restored vascular integrity by SalB via modulating the interactions between tumor cells and endothelial cells (ECs) offered a principal route for achieving vascular normalization. Taken together, our data elucidated that SalB enhanced sensitivity of tumor cells to chemotherapy and immunotherapy through triggering tumor vascular normalization, providing a potential therapeutic strategy of combining SalB and chemotherapy or immunotherapy for patients with breast cancer.

Abstract 1845: Exploring the mode of action of a highly efficacious ruthenium-based chemotherapeutic agent in triple negative breast cancer

Abstract Purpose: Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is defined by the absence of expression of progesterone receptor, estrogen receptor, and human epidermal growth factor receptor 2. TNBC has a higher incidence in younger women and those of African descent. Due to the inability to target a receptor, treatment is mostly limited to anthracycline and taxane-based nonspecific chemotherapy. Within the past two years more therapies have become available for later stage TNBC, such as antibody-drug conjugate sacituzumab govitecan-hziy. A potential water-soluble ruthenium-based chemotherapeutic agent was developed in our lab, showing high cytotoxicity against different cancer types in a National Cancer Institute 60-cell line panel. A preliminary in vivo study of this complex showed a pronounced 56% reduction of tumor growth with a TNBC MDA-MB-231 cell line xenograft mouse model, with little system toxicity and preferential accumulation of the complex in tumor tissue. These studies prompted us to further evaluate it in TNBC cell lines MDA-MB-231 and HCC-1806, derived from Caucasian and African ancestry patients respectively. This investigation revealed significant anti-angiogenic, anti-invasive, and anti-migratory properties for the complex, along with subcellular accumulation in the mitochondria and an apoptotic mechanism of cell death in both cell lines. Preliminary proteomic analysis was completed to understand the molecular pathway involved, which was determined to be P53-independent. Macrophage colony stimulating factor (M-CSF) showed an inhibition of protein expression, implicating the ruthenium complex as a potential inhibitor of phosphoinositide 3-kinases/protein kinase B (PI3K/Akt) pathway which acts downstream of M-CSF, and is involved with enhanced cancerous proliferation. In light of these findings, we report here on in vitro studies focused on further investigating the involvement of the PI3K/Akt molecular pathway and mechanism of action of this ruthenium complex. Experimental Design: Western blot studies directed toward key markers in the PI3K/Akt pathway will be assessed, which include Akt, c-Raf, PI3K, PTEN, and PDK1. Furthermore, mitochondrial involvement was determined through reactive oxygen species (ROS) generation and changes to mitochondrial membrane potential (MMP). Results: A significant increase of ROS generation was seen with exposure to the compound, along with slight MMP depolarization. Western blot analysis may further implicate an inhibition of the PI3K/Akt pathway. Conclusions: Our results show that the mechanistic action of the tested ruthenium complex has mitochondrial involvement, with inhibitory effects in the PI3K/Akt pathway. The very significant anti-cancer properties outlined in the preclinical evaluation of this complex will be further investigated in PDX mice models. Citation Format: Nazia Nayeem, Karen Hubbard, Maria Contel. Exploring the mode of action of a highly efficacious ruthenium-based chemotherapeutic agent in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1845.

Abstract 385: iRGD mediated delivery of neoantigens to enable immunotherapy in integrin b5-rich tumors

Abstract Pancreatic duct adenocarcinomas are known for their abundant desmoplastic stroma that acts as a barrier for drug penetration and reduces treatment efficacy. iRGD is a tumor-penetrating peptide that initially targets αv integrins expressed on tumor vasculature with its RGD motif and then is proteolytically processed to expose a CendR motif (R/KXXR/K) that interacts with neuropilin-1 (NRP-1), leading to extravasation. We investigated the mechanism of iRGD tissue penetration and found that iRGD initially targets Carcinoma Associated Fibroblasts (CAFs) and then spreads to the tumor cells in a time dependent manner. CAF targeting was dependent on integrin β5 expression and CAFs induced upregulation of integrin β5 in the adjacent tumor cells in a TGF- β dependent manner. Drugs conjugated or co-administered with iRGD can penetrate deep into tumor tissue, significantly increasing the efficacy of chemotherapeutic agents in a variety of solid tumors. Our recent data shows that KrasLSL-G12D/+ Trp53LSL-R172H/+ Pdx1-Cre (KPC) mice treated with iRGD co-administered with Gemcitabine increased survival compared to drug alone. In addition, we are using iRGD to deliver neoantigens to breast and pancreatic cancers to enable immunotherapy. These tumors have a low mutational burden and a very immunosuppressive microenvironment, rendering them resistant to such therapies. We have used iRGD, to deliver the ovalbumin 257-264 (OVAI) peptide to triple negative breast tumors, followed by adoptive T cell transfer of OT1 CD8 T cells, in order to elicit an antitumor immune response. Our preliminary data showed tumor regression in 70%, and complete response in 42% of the mice treated with iRGD plus OVA1. We are now working on adapting this strategy to pancreatic cancer. Citation Format: Tatiana Hurtado de Mendoza, Evangeline S. Mose, Gregory P. Botta, Gary B. Braun, Venkata R. Kotamraju, Randall P. French, Kodai Suzuki, Norio Miyamura, Siming Sun, Jay Patel, Tambet Teesalu, Erkki Ruoslahti, Kazuki N. Sugahara, Andrew M. Lowy. iRGD mediated delivery of neoantigens to enable immunotherapy in integrin b5-rich tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 385.

Abstract 6349A: Mechanical stress activates autophagy to induce drug resistance in pancreatic cancer cells

Abstract INTRODUCTION: One of the most fundamental problems that oncologists are currently facing in pancreatic cancer patient care is the high resistance to all types of chemotherapies or targeted therapies. Thus, there is an urgent need for increasing patient response to treatment. A common characteristic among most pancreatic cancer patients that could serve as potential target for treatment, is the biomechanically abnormal tumor microenvironment (TME). This altered TME is characterized by an increased stiffness which among others, is responsible for the development of mechanical stresses in the tumor interior. Even though several studies have investigated the effect of mechanical stress on cancer cells and tumor progression, it has not yet defined whether it can affect drug sensitivity and what are the mechanisms involved. HYPOTHESIS: Based on our recent findings, obtained by a Reverse Phase Protein Assay, we observed that mechanical stress activates a resistance response, employing autophagy activation, in pancreatic cancer cells. To this end, we hypothesize that mechanical stress developed during tumor growth, can induce autophagy activation to eventually promote drug resistance in pancreatic tumors. Therefore, inhibition of this mechanism can improve therapy. METHODOLOGY: We use two pancreatic cancer cells lines, MIA PaCa-2 and PANC-1, to apply mechanical stress, either in a 2D experimental setup or by employing tumor spheroids in a 3D agarose matrix. In both cases, cells are exposed to the most common chemotherapeutic agents used for pancreatic cancer treatment, gemcitabine and 5-Fluorouracil (5FU). The cytotoxic effect of each drug, as well as autophagy- and signaling pathway- activation are then analyzed. Finally, in vitro assays and treatments, along with in vivo animal models of pancreatic tumors, are performed to test the efficacy of an autophagy inhibitor combined with chemotherapy and a mechanotherapeutic that modulates intratumoral mechanical stresses. RESULTS: Proteomic analysis, together with pharmacological inhibition and siRNA treatments, revealed that mechanical stress activates autophagy to impair cell apoptosis and promote cancer cell survival. This stress-adaptation mechanism in turn impairs the cytotoxic effect of both gemcitabine and 5FU. A combined treatment employing chemotherapy with an autophagy inhibitor, and a mechanotherapeutic agent, showed promising results in increasing the overall-survival of pancreatic tumor-bearing mice. CONCLUSION: Our results provide solid evidence that alleviation of intratumoral mechanical stresses with mechanotherapeutics combined with autophagy inhibitors can improve the efficacy of chemotherapeutic agents in pancreatic cancer. Citation Format: Maria Kalli, Ruxuan Li, Ioannis Zervantonakis, Triantafyllos Stylianopoulos. Mechanical stress activates autophagy to induce drug resistance in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6349A.

Investigating β‐Lapachone Mediated Metabolic Disruption Using Stable Isotope Tracers

β‐lapachone has been found to be a highly potent anti‐cancer agent in phase 1 clinical trials, but has dose limiting toxicity in red blood cells [Gerber et. al Br J Cancer. 2018 Oct;119(8):928‐936]. Identifying a safe and quantitative method of monitoring treatment efficacy will be highly beneficial to establishing an adaptive dosing platform. Adaptative dosing can allow personalized treatments that significantly reduce off target effects while maintaining an effective therapeutic regimen. In this study we present the use of a safe and noninvasive tracer strategy utilizing both [2H7]glucose and [U‐13C]glucose tracers to assess the metabolic effects caused by β‐lapachone treatment in vitro. Treating cancers with β‐lapachone bioactivates NAD(P)H: quinone oxidoreductase 1 (NQO1) to produce a highly unstable hydroquinone intermediate that reestablishes itself through an aggressive futile cycle, generating reactive oxygen species (ROS) in the form of hydrogen peroxide. Accelerated accumulation of ROS causes large amounts of DNA damage, triggers poly‐ADP‐ribose polymerase‐I hyperactivation, induces global depletion of NAD+ and ATP, and hinders overall glycolytic flux [Moore et. al Cell Death Dis. 2015 Jan; 6(1): e159]. Cancer cells that overexpress NQO1 subsequently die through NAD+‐keresis. Measuring changes in glycolysis and downstream metabolism caused by the bioactivation of NQO1 would establish a platform for assessing the efficacy of treatment, potentially allowing the reduction of chemotherapeutic dosage thereby diminishing off‐target toxicities. Changes in central carbon metabolism caused by NQO1 bioactivation were detected and assessed in various cancer cells using both tracer strategies. Deuterated lactate and HDO (deuterated water) were easily quantified, and the production of these metabolic products were linearly correlated with [2H7]glucose consumption. Mass isotopologue distribution analysis by gas chromatography‐mass spectrometry demonstrated downregulated energy metabolism with a reduction in 2H and 13C labeling in NQO1+ cancer cells treated with β‐lapachone. These methods are highly beneficial for measuring rates of glycolytic metabolism, identifying potential therapeutic synergies, the efficacy of chemotherapeutic agents that hamper central carbon metabolism, and can be potentially translated to in vivo models.

Novel numerical investigation of the fractional oncolytic effectiveness model with M1 virus via generalized fractional derivative with optimal criterion

Oncolytic virotherapy is an efficacious chemotherapeutic agent that addresses and eliminates cancerous tissues by employing recombinant infections. M1 is a spontaneously produced oncolytic alphavirus with exceptional specificity and powerful activity in individual malignancies. The objective of this paper is to develop and assess a novel fractional differential equation (FDEs)-based mathematical formalism that captures the mechanisms of oncogenic M1 immunotherapy. The aforesaid framework is demonstrated with the aid of persistence, originality, non-negativity, and stability of systems. Additionally, we also examine all conceivable steady states and the requirements that must exist for them to occur. We also investigate the global stability of these equilibria and the characteristics that induce them to be unstable. Furthermore, the Atangana–Baleanu fractional-order derivative is employed to generalize a treatment of the cancer model. This novel type of derivative furnishes us with vital understanding regarding parameters that are widely used in intricate mechanisms. The Picard–Lindelof approach is implemented to investigate the existence and uniqueness of solutions for the fractional cancer treatment system, and Picard’s stability approach is used to address governing equations. The findings reveal that the system is more accurate when the fractional derivative is implemented, demonstrating that the behaviour of the cancer treatment can be interpreted when non-local phenomena are included in the system. Furthermore, numerical results for various configurations of the system are provided to exemplify the established simulation.

Cytotoxicity and Apoptosis-Induction Potential of Fraction F3 from Fruits of Bersama engleriana (Melanthaceae) against Human Cervical Cancer Cells

Cervical cancer is one of the most life-threatening malignancies worldwide, despite intensive research for more efficacious chemotherapeutic agents. Recent efforts geared towards eradicating the scourge of cancer have embodied a major surge of interest in natural products as promising lead molecules in pharmaceutical development and therapeutic translation. Consequently, this study aimed to assess the cytotoxicity of a previously identified plant Fraction (F3) from Bersama engleriana against cervical cancer (HeLa) cells and non-cancerous normal human foreskin fibroblasts (HFF cells). Flow cytometric analysis via Annexin V/PI in HeLa cells was carried out to assess apoptosis induction. We report here the 50% Inhibitory Concentration (IC50) of fraction F3 to be 96.15 µg/mL and a 50% Cytotoxic Concentration (CC50) of 527.4 µg/mL, as well as a Selectivity Index (SI) of 5.48, thus confirming that fraction F3 is relatively non-toxic to the normal cells compared to the cancer cells evaluated. In addition, microscopic observations showed a higher reduction of cells, aggregated with dark color in HeLa cells treated with fraction F3 compared to control (cells only). The Annexin V/PI analysis showed the percentages of apoptotic cells were 4.6±0.05, 7.9±0.9 and 7.6±0.15, respectively, for the control and treatments of cells with 120 and 150 µg/mL fraction F3 in early apoptosis (Annexin V+/PI-) 48 h post-treatment. Percentages of apoptotic cells were 2.1±0.1, 8.9±0.2 and 7.7±0.2, respectively, for control, 120 and 150 µg/mL fraction F3 treatments in late apoptosis (Annexin V+/PI+) after 48 h posttreatment. Nevertheless, a comparison of the lowest percentage inhibition of apoptosis with the highest number of reduced cells observed with fluorescence microscopy suggests that fraction F3 may exert its growth inhibitory action on HeLa cells via another mechanism. The results established that fraction F3 from B. engleriana is a promising source for exploring antitumor activity.

Cannabis with breast cancer treatment: propitious or pernicious?

The online version contains supplementary material available at 10.1007/s13205-021-03102-1.

Biofabrication of Gold Nanoparticles Using Capsicum annuum Extract and Its Antiquorum Sensing and Antibiofilm Activity against Bacterial Pathogens.

The intensive use of antimicrobial agents has led to the emergence of multidrug resistance (MDR) among microbial pathogens. Such microbial (MDR) infections become more problematic in chronic diseases in which the efficacy of chemotherapeutic agents is highly reduced. To combat the problem of drug resistance, inhibition of bacterial quorum sensing (QS) and biofilms are considered as promising strategies in the development of anti-infective agents. In this study, gold nanoparticles (AuNPs-CA) were biofabricated using Capsicum annuum aqueous extract and characterized. The AuNPs-CA were tested against the QS-controlled virulence factors and biofilms of Pseudomonas aeruginosa PAO1 and Serratia marcescens MTCC 97. AuNPs-CA were found to be crystalline in nature with average particle size 19.97 nm. QS-mediated virulent traits of P. aeruginosa PAO1 such as pyocyanin, pyoverdin, exoprotease activity, elastase activity, rhamnolipids production, and swimming motility were reduced by 91.94, 72.16, 81.82, 65.72, 46.66, and 46.09%, respectively. Similarly, dose-dependent inhibition of virulence factors of S. marcescens MTCC 97 was recorded by the treatment of AuNPs-CA. The biofilm development and exopolysaccharide (EPS) production also decreased significantly. Microscopic analysis revealed that the adherence and colonization of the bacteria on solid support were reduced to a remarkable extent. The findings indicate the possibility of application of green synthesized gold nanoparticles in the management of bacterial infection after careful in vivo investigation.

Interaction between CD9 and PI3K‑p85 activates the PI3K/AKT signaling pathway in B‑lineage acute lymphoblastic leukemia.

Our previous study has shown that CD9 knockdown could suppress cell proliferation, adhesion, migration and invasion, and promote apoptosis and the cytotoxicity of chemotherapeutic drugs in the B‑lineage acute lymphoblastic leukemia (B‑ALL) cell line SUP‑B15. In this study, we further investigated the molecular mechanism underlying the effects of CD9 on leukemic cell progression and the efficacy of chemotherapeutic agents in B‑ALL cells. Using the CD9‑knockdown SUP‑B15 cells, we demonstrated that the silencing of the CD9 gene significantly reduced the expression of phosphorylated‑phosphatidylinositol‑3 kinase (p‑PI3K), phosphorylated‑protein kinaseB(p‑AKT), P‑glycoprotein(P‑gp), multidrug resistance‑associated protein1(MRP1), breast cancer resistance protein (BCRP), matrix metalloproteinase2 (MMP2) and phosphorylated‑focal adhesion kinase(p‑FAK). In addition, glutathione S‑transferase (GST) pull‑down assay showed the binding between CD9 and both PI3K‑p85α and PI3K‑p85β invitro, while co‑immunoprecipitation assay showed the binding between CD9 and both PI3K‑p85α and PI3K‑p85β invivo. Furthermore, the PI3K/AKT inhibitor LY294002 mirrored the effects of CD9 knockdown in SUP‑B15 cells. Taken together, these findings demonstrated that CD9 activates the PI3K/AKT signaling pathway through direct interaction with PI3K‑p85 in B‑ALL cells. Our data provide evidence for the inhibition of the PI3K/AKT pathway as a novel therapeutic option in CD9 antigen‑positive B‑ALL.

A novel radiolytic rotenone derivative, rotenoisin A, displays potent anticarcinogenic activity in breast cancer cells.

Chemotherapy for cancer treatment has therapeutic limitations, such as drug resistance, excessive toxic effects and undesirable adverse effects. Therefore, efforts to improve the safety and efficacy of chemotherapeutic agents are essential. Ionizing radiation can improve physiological and pharmacological properties by transforming structural modifications of the drug. In this study, in order to reduce the adverse effects of rotenone and increase anticancer activity, a new radiolytic rotenone derivative called rotenoisin A was generated through radiolytic transformation. Our findings showed that rotenoisin A inhibited the proliferation of breast cancer cells and increased the rate of apoptosis, whereas it had no inhibitory effect on primary epidermal keratinocytes compared with rotenone. Moreover, rotenoisin A-induced DNA damage by increasing reactive oxygen species (ROS) accumulation. It was also confirmed not only to alter the composition ratio of mitochondrial proteins, but also to result in structural and functional changes. The anticancer effect and molecular signalling mechanisms of rotenoisin A were consistent with those of rotenone, as previously reported. Our study suggests that radiolytic transformation of highly toxic compounds may be an alternative strategy for maintaining anticancer effects and reducing the toxicity of the parent compound.

Copper-lowering agents as an adjuvant in chemotherapy.

Copper is an important element essential for metabolism and normal human body function. Although it is an essential element, related imbalance leads to toxic effects. Studies have proved that there is an increase in copper level in cancer cells. Evidences suggest the link between increase in copper levels and progression of various types of cancers. Different strategies have been utilized to decrease the level of copper in various types of cancer cells. However, it was observed that cell machinery involved in copper homeostasis plays critical factor in lowering copper levels in cancer cells. The outcomes of many monotherapies consisting copper-lowering agents for the treatment of different types of cancers showed that the inhibition of single factor is not sufficient to inhibit the growth of cancer cells. The combination of copper-lowering agent with chemotherapeutic agent showed synergistic effect. Interestingly, the presence of copper-lowering agent in such combinations significantly improved the efficacy of chemotherapeutic agent. The present work has focused on the discussion of outcomes of studies involving anti-copper agent and chemotherapeutic agent and related future strategies.

Activation of the Aryl Hydrocarbon Receptor (AHR) induces human glutathione S transferase alpha 1 (hGSTA1) expression

Glutathione S-transferases (GSTs) are a key enzyme superfamily involved in the detoxification and cytoprotection of a wide variety of xenobiotics, such as carcinogens, anticancer drugs, environmental toxicants, and endogenously produced free radicals. In the liver, the hGSTA1 isoenzyme is the most abundant and catalyzes the glutathione conjugation of a wide range of electrophiles and has been the principal GST responsible for xenobiotic detoxification. Given the critical role of this enzyme in several cellular processes, particularly cell detoxification, understanding the molecular mechanisms underlying the regulation of hGSTA1 expression is critical. Therefore, the aim of the present study was to investigate whether AHR is involved in the modulation of hGSTA1 gene expression and to characterize the molecular mechanism through which AHR exerts this regulation. Two xenobiotic response elements (XREs) were located at −602 bp and −1030 bp from the transcription start site at the hGSTA1 gene promoter. After treatment of HepG2 cells with beta-naphthoflavone (β-NF), an AHR agonist, induction of hGSTA1 mRNA was observed. This effect was mediated by the recruitment of AHR to the hGSTA1 gene promoter and its transactivation, as indicated by the ChIP, EMSA and luciferase activity assays. The increase in hGSTA1 transcription regulated by AHR also resulted in enhanced levels of hGSTA1 protein and activity. Taken together, our data suggest that AHR ligands have the potential to modify xenobiotic and endobiotic metabolism mediated by hGSTA1, thereby altering the detoxification of xenobiotics, steroidogenesis and the efficacy of chemotherapeutic agents.

Genetic Diversity of Schistosoma haematobium in Qena Governorate, Upper Egypt.

IntroductionSchistosomiasis is an important neglected tropical disease (NTD) in several developing countries. Praziquantel is the principle and efficacious chemotherapeutic agent that has been used to treat schistosomiasis for decades. Unfortunately, emerging resistance to praziquantel with accompanying reduced efficacy is reported in some localities. Hence, genetic diversity among parasite populations is of significant interest in assessing the effects of selective pressure generated by praziquantel therapy that might result in encouraging the emergence of new genotypes that are either non-susceptible or drug-resistant. The present study aimed to investigate the genetic diversity of Schistosoma haematobium among human populations using the RAPD technique to help clarify disease epidemiology and transmission.Materials and MethodsS. haematobium eggs were isolated from 50 of 134 patients from four different localities in Qena Governorate, Upper Egypt. These patients complained of terminal hematuria and burning micturition. Samples were used for molecular analysis using RAPD-PCR primers (A02, A07, A09, A10).ResultsTwenty S. haematobium isolates (40%) were amplified using the selected RAPD primers. Amplification patterns of these isolates showed distinct variation in the size and number of amplified fragments, indicating high genetic variation among these isolates.ConclusionTo the best of our knowledge, this study is the first to characterize the genetic diversity of S. haematobium in human populations in Upper Egypt. Future studies on a larger geographic scale involving many districts in Upper Egypt should be encouraged. Information from such a study would provide better insight into clonal lineages of S. haematobium in this endemic area. In turn, understanding transmission of the parasite may have a major role in establishing control strategies for urogenital schistosomiasis in Upper Egypt.

Application prospect of peptide-modified nano targeting drug delivery system combined with PD-1/PD-L1 based immune checkpoint blockade in glioblastoma

Glioblastoma (GBM) is a type of primary malignant brain tumor with low median survival time, high recurrence rate and poor prognosis. The blood-brain barrier (BBB) and the diffuse infiltration of invasive GBM cells lead to a lower efficacy of traditional treatment. Recently, nanocarriers have become a promising method of brain drug delivery due to their ability to effectively cross the BBB. Especially, the peptide-modified nanocarriers can enhance the permeability, targeting and efficacy of chemotherapeutic agents against GBM. Moreover, the clinical application of immune checkpoint blockade (ICB) therapy in cancer treatment has attracted increasing attention, and the programmed death-1 receptor (PD-1) and PD-ligand-1 (PD-L1) monoclonal antibodies are considered to be a possible therapy for GBM. Consequently, we review the advances both in peptide-modified nano targeted drug delivery system and PD-1/PD-L1 based ICB in GBM treatment, and propose a new strategy combining the two methods, which may provide a novel approach for GBM treatment.

Pristimerin Exacerbates Cellular Injury in Conditionally Reprogrammed Patient-Derived Lung Adenocarcinoma Cells by Aggravating Mitochondrial Impairment and Endoplasmic Reticulum Stress through EphB4/CDC42/N-WASP Signaling.

Lung cancer is the most common and lethal malignant disease for which the development of efficacious chemotherapeutic agents remains an urgent need. Pristimerin (PRIS), a natural bioactive component isolated from various plant species in the Celastraceae and Hippocrateaceae families, has been reported to exhibit outstanding antitumor effects in several types of cells. However, the underlying mechanisms involved remain poorly understood. Here, we reported the novel finding that PRIS significantly suppressed lung cancer growth in conditionally reprogrammed patient-derived lung adenocarcinoma cells (CRLCs). We demonstrated that PRIS inhibited the cell viabilities, migrative and invaded abilities, and capillary structure formation of CRLCs. Furthermore, our results clarified that PRIS induced mitochondrial dysfunction through reactive oxygen species (ROS) generation, activation of caspase-9, caspase-3, and caspase-4, and expression of endoplasmic reticulum (ER) stress-associated proteins. Inhibition of ER stress by 4-PBA (4-phenylbutyric acid, a specific ER stress inhibitor) or CHOP siRNA transfection ameliorated PRIS-induced loss of mitochondrial membrane potential and intrinsic apoptosis. The present study also provides mechanistic evidence that PRIS suppressed the EphB4/CDC42/N-WASP signaling pathway, which is required for mitochondrial-mediated intrinsic apoptosis, activation of ER stress, and stimulation of caspase-4 induced by PRIS, and consequently resulting in suppressed cell viability, migration, and angiogenesis in CRLCs. Taken together, by providing a mechanistic insight into the modulation of ER stress-induced cell death in CRLCs by PRIS, we suggest that PRIS has a strong potential of being a new antitumor therapeutic agent with applications in the fields of human lung adenocarcinoma.