Cytotoxic Chemotherapeutic Drugs Research Articles

Occurrence of respiratory and urinary tract infections in patients treated with docetaxel compared with afatinib based on a health insurance claims database in Japan.

The relative occurrence of infection in patients treated with cytotoxic chemotherapeutic drugs and molecularly targeted drugs is unclear. To compare the occurrence of respiratory and urinary tract infections in patients treated for lung cancer with docetaxel versus afatinib and to predict the occurrence of the respiratory and urinary tract infections. Data on patients who received docetaxel or afatinib were obtained from a health insurance claims database. After propensity score matching, the occurrence of respiratory and urinary tract infections in each group was compared. Factors associated with respiratory and urinary tract infections were evaluated using multivariable conditional logistic regression analysis. Each group included 855 patients. The occurrence of respiratory infections was significantly higher in the docetaxel group than in the afatinib group (22.6% [193/855] vs. 13.9% [119/855]; p < 0.01). The occurrence of urinary tract infections did not differ significantly by group. Docetaxel was independently associated with a significantly increased risk of respiratory infections (adjusted odds ratio: 1.68, 95% confidence interval: 1.23-2.29), but not urinary tract infections. Patients with lung cancer treated with docetaxel should be closely monitored for the occurrence of respiratory infection in clinical settings.

Cytotoxic effects of nerve growth factor and its combinations with chemotherapeutic drugs on anaplastoc astrocytoma, glioblastoma and medubloblastoma cells &lt;i&gt;in vitro&lt;/i&gt;

BACKGROUND: Currently, the effectiveness of the treatment of malignant tumors using surgical resection, radiotherapy and chemotherapy is insufficient. Therefore, new research is needed to find alternative molecules with antitumor effects. It is known that nerve growth factor (NGF) inhibits invasion, migration, and angiogenesis of tumor cells. Studying the effects of NGF on brain tumors, as well as its combinations with chemotherapy drugs used in medicine, may contribute to the development of new treatment regimens for malignant neoplasms in the central nervous system. AIM: The purpose of this study is an exploration the molecular and cellular mechanisms of anticancer effects of individual and combined preparations of NGF and chemotherapeutic drugs on brain tumor cells (gliomas C6, U251, anaplastic astrocytoma, glioblastoma and medulloblastoma). MATERIALS AND METHODS: The study was performed on rat glioma C6, human U251 glioma cell lines, as well as on primary cells of anaplastic astrocytoma (n = 9), glioblastoma (n = 9) and medulloblastoma (n = 38) patients. The cytotoxicity of chemotherapeutic drugs, NGF and their combinations against tumor cells was assessed using the MTT assay. The expression of TrkA and p75 receptors on anaplastic astrocytoma, glioblastoma and medulloblastoma cells was assessed by immunofluorescence analysis using anti-TrkA and anti-p75 monoclonal antibodies. RESULTS: Nerve growth factor exhibits in vitro cytotoxic activity that exceeds the activity of chemotherapy drugs towards rat glioma C6, human U251, anaplastic astrocytoma (AA), glioblastoma (GBM) and medulloblastoma cells. The cytotoxic activity of NGF in combination with chemotherapy drugs is significantly higher than the activity of the individual NGF drug against medulloblastoma cells, while against anaplastic astrocytoma cells it is comparable to the indicators of the isolated action of NGF, and lower for glioblastoma cells. The effectiveness of the cytotoxic effect of the combinations NGF + cisplatin and NGF + temozolomide (TMZ) on AA and GBM cells correlates with both the expression of TrkA, p75 receptors, and their coexpression, indicating that expression indicators can be considered as markers of tumor cell sensitivity to NGF. CONCLUSIONS: The data obtained allow us to consider NGF as a potential anticancer drug for the treatment of brain tumors. Thus, NGF can act as a potential anticancer drug for the development of new therapeutic regimens for brain tumors.

Protective Effects of Chia Seeds and Omega-3 Fatty Acid against Cyclophosphamide-Induced Oligospermia in Male Wistar Rats: Potential Risks of Adverse Drug Interaction with Chia Seeds.

Objectives: The aim of this study was to investigate whether chia (Salvia hispanica) seeds, which are rich in omega-3 fatty acids, amino acids, and vitamins with antioxidant properties, can mitigate the negative effects on male reproductive function caused by cyclophosphamide, a frequently used chemotherapeutic agent. Methods: Male wistar rats are divided into seven groups (n=6). All groups except the normal control (NC) received cyclophosphamide (30mg/kg, i.p.) for the first 5 days. The standard group received clomiphene citrate (0.25 mg/kg, p.o.). Treatment groups T1%, T5%, T10%, and ω-3 received 1%, 5%, and 10% chia seeds in the diet, and 880 mg/kg omega-3 fatty acid (p.o) respectively for 15 days. The effect on the reproductive system was evaluated by analysis of epididymal sperm characteristics, biochemical parameters, and serum testosterone level. Results: Clomiphene citrate improved oligospermia via hormone mediated effect. Chia seeds and omega-3 fatty acid treatment also showed improvement in reproductive parameters including oxidative stress and histological features of the testes. Omega-3 fatty acid treatment was more effective for the prevention of cyclophosphamide toxicity on testes as compared to chia seeds. Nasal bleeding was noted in several animals subjected to chia seed treatment. This occurrence might be attributed to chia seeds' impact on coagulation and/or platelet function, potentially heightened due to chemotherapy associated bone marrow suppression. Conclusions: In our study, chia seeds as well as omega-3 fatty acid treatment were found to be protective against cyclophosphamide-induced reproductive toxicity in rats. However, the adverse effect of hemorrhage associated with drug interaction of chia seeds with cytotoxic chemotherapeutic drugs needs careful attention and further investigation.

A Prospective, Multicenter, Observational Registry (ReCoRD) on Demography, Molecular Profile, Clinical Features, and Treatment Outcomes in Individuals undergoing Treatment for Metastatic Colorectal Cancer

Objective: Out of all newly diagnosed colorectal cancer cases globally, 20% of the patients present with metastasis, and 25% develop metastasis later. The 5-year survival rate after diagnosis for mCRC patients is &lt;20%. Although many studies using population-based cancer registries from India are available on various cancers, data on mCRC in India is scarce. Therefore, the purpose of the ReCoRD registry is to obtain real world data on demographics, treatment pattern and outcomes in Indian patients with mCRC. Methods: This is a prospective, multicenter, observational study on 1000 participants with mCRC, who are enrolled in the registry in up to 15 centers for 2 years. The recruitment will be stopped 2 years following the first patient enrollment. A minimum follow-up of 12–18 months is being carried out post-enrollment in the registry. Data on the demography, clinical features, molecular profile, treatment options, and outcomes of treatment for these patients is being collected from the study sites by investigators. The Kaplan-Meier Plot will be utilized to examine the survival data, and the median time computed by the Kaplan-Meier technique will be presented with a confidence interval of 95%.Conclusion: Although mCRC remains incurable in most cases, survival rates have improved with the advent of newer cytotoxic chemotherapeutic drugs and targeted agents. The ReCoRD registry will collect details of the demography, tumor characteristics, molecular aspects, treatment, and treatment outcomes in individuals with mCRC, which can guide the clinicians in decision making and treatment based on Indian patient data.

Anticancer effect of metformin alone and in combination with 2-deoxy-D-glucose on mouse T cell lymphoma EL4 cells

Metformin is a treatment used widely for non-insulin-dependent diabetes mellitus with few side effects and acts by inhibiting hepatic gluconeogenesis and glucose absorption from the gastrointestinal tract. Lymphoma is one of the most common hematological malignancies in dogs. Chemotherapy is used mainly on lymphoma, but further research on developing anticancer drugs for lymphoma is needed because of its severe side effects. This study examined the anticancer effects of metformin alone and in combination with 2-deoxy-D-glucose (2-DG), a glucose analog, on EL4 cells (mouse T-cell lymphoma). Metformin reduced the metabolic activity of EL4 cells and showed an additive effect when combined with 2-DG. In addition, cell death was confirmed using a trypan blue exclusion test, Hochest 33342/propidium iodide (PI) staining, and Annexin V/PI staining. An analysis of the cell cycle and mitochondria membrane potential (MMP) to investigate the mechanism of action showed that metformin stopped the G2/M phase of EL4 cells, and metformin + 2-DG decreased MMP. Metformin exhibited anticancer effects as a G2/M phase arrest mechanism in EL4 cells and showed additive effects when combined with 2-DG via MMP reduction. Unlike cytotoxic chemotherapeutic anticancer drugs, metformin and 2-DG are related to cellular glucose metabolism and have little toxicity. Therefore, metformin and 2-DG can be an alternative to reduce the toxicity caused by chemotherapeutic anticancer drugs. Nevertheless, research is needed to verify the in vivo efficacy of metformin and 2-DG before they can be used in lymphoma treatments.

Sertraline as a potential cancer therapeutic approach: Biological relevance of TCTP in breast cancer cell lines and tumors

PurposeThis study aimed to evaluate the role of Translationally Controlled Tumor Protein (TCTP) in breast cancer (BC) and investigate the effects of sertraline, a serotonin selective reuptake inhibitor (SSRI), on BC cells. The objective was to assess the potential of sertraline as a therapeutic agent in BC treatment by examining its ability to inhibit TCTP expression and exert antitumor effects. Material and MethodsWe utilized five different BC cell lines representing the molecular heterogeneity and distinct subtypes of BC, including luminal, normal-like, HER2-positive, and triple-negative BC. These subtypes play a crucial role in determining clinical treatment strategies and prognosis. ResultsThe highest levels of TCTP were observed in triple-negative BC cell lines, known for their aggressive behavior. Sertraline treatment reduced TCTP expression in BC cell lines, significantly impacting cell viability, clonogenicity, and migration. Additionally, sertraline sensitized triple-negative BC cell lines to cytotoxic chemotherapeutic drugs (doxorubicin and cisplatin) suggesting its potential as an adjunctive therapy to enhance the chemotherapeutic response. Bioinformatic analysis of TCTP mRNA levels in TCGA BC data revealed a negative correlation between TCTP levels and patient survival, as well as between TCTP/tpt1 and Ki67. These findings contradict our data and previous studies indicating a correlation between TCTP protein levels and aggressiveness and poor prognosis in BC. ConclusionsSertraline shows a promise as a potential therapeutic option for BC, particularly in triple-negative BC. Its ability to inhibit TCTP expression, enhance chemotherapeutic response, highlights its potential clinical utility in BC treatment, specifically in triple-negative BC subtype.

Methylselenocysteine Promotes Etoposide Cytotoxicity by Enhancing Homotypic Gap Junctions Composed of Connexin 26

To investigate the effect of methylselenocysteine (MSC) on the function of homotypic gap junction (GJ) composed of connexin (Cx) 26 and its regulation of chemotherapeutic drug cytotoxicity. The Tet-on HeLa cells transfected with and stably expressing Cx26 were used as the tool cells. Effects of MSC on cell growth, GJ function, and Cx26 protein expression were examined by MTT method, parachute assay, and Western blot analysis, respectively. The cytotoxicity of chemotherapeutic drugs was determined by standard colony-forming assay, and the relationship between MSC's effect on cytotoxicity of these chemotherapeutic drugs and its regulation of GJ was further analyzed. In Tet-on HeLa cells, doxycycline (Dox) can induce the expression of Cx26, which could then form functional GJs. Within a concentration range of 50 μmol/L, MSC had no significant effect on HeLa cell growth. Non-toxic concentrations of MSC can enhance GJs in a concentration-dependent manner and exert its effect at the nanomolar level. This effect was associated with an induction of Cx26 protein expression by MSC. Among the three common chemotherapeutic agents with different mechanisms of action, etoposide (Eto) presented cytotoxicity differences between HeLa cells cultured at low density (nonconfluent, no GJ formed) and high density (confluent, GJ formed). What's more, the inhibitory effect of Eto combined with MSC on HeLa cell colony formation was stronger than that of Eto alone, and this effect occurred only in HeLa cells with GJ formation. MSC can potentiate the cytotoxicity of Eto by enhancing the GJs composed of Cx26, indicating that combined strategy of selenide and chemotherapy shows potential value in the treatment of malignant tumors.

AKT inhibitor Hu7691 induces differentiation of neuroblastoma cells.

While neuroblastoma accounts for 15% of childhood tumor-related deaths, treatments against neuroblastoma remain scarce and mainly consist of cytotoxic chemotherapeutic drugs. Currently, maintenance therapy of differentiation induction is the standard of care for neuroblastoma patients in clinical, especially high-risk patients. However, differentiation therapy is not used as a first-line treatment for neuroblastoma due to low efficacy, unclear mechanism, and few drug options. Through compound library screening, we accidently found the potential differentiation-inducing effect of AKT inhibitor Hu7691. The protein kinase B (AKT) pathway is an important signaling pathway for regulating tumorigenesis and neural differentiation, yet the relation between the AKT pathway and neuroblastoma differentiation remains unclear. Here, we reveal the anti-proliferation and neurogenesis effect of Hu7691 on multiple neuroblastoma cell lines. Further evidence including neurites outgrowth, cell cycle arrest, and differentiation mRNA marker clarified the differentiation-inducing effect of Hu7691. Meanwhile, with the introduction of other AKT inhibitors, it is now clear that multiple AKT inhibitors can induce neuroblastoma differentiation. Furthermore, silencing AKT was found to have the effect of inducing neuroblastoma differentiation. Finally, confirmation of the therapeutic effects of Hu7691 is dependent on inducing differentiation invivo, suggesting that Hu7691 is a potential molecule against neuroblastoma. Through this study, we not only define the key role of AKT in the progression of neuroblastoma differentiation but also provide potential drugs and key targets for the application of differentiation therapies for neuroblastoma clinically.

RETRACTED: Neuroprotective potential of Ginkgo biloba on alteration of rat cerebellum following prenatal exposure to cyclophosphamide

The cytotoxicity of chemotherapeutic drugs is known due to its non-selective effect not only on cancer cells but also on healthy cells. This study investigated the cerebellar alteration in rats prenatally exposed to cyclophosphamide (SK, 20 mg/kg). We also evaluated the neuroprotective potential of Ginkgo biloba (GB, 80 mg/kg/day) against possible biological changes caused by SK in the cerebellar tissues. Twenty adult female rats (weighing 230–280 g, 12 weeks old) were divided into five groups: control, sham, SK, GB, and SK + GB. After mating, pregnant rats was treated with SK in the SK and SK + GB groups and GB in the GB and SK + GB groups from day 13 to day 21 of gestation. After parturition, eight female rats were randomly selected from each group. On day 32 after birth, the cerebellar tissues were dissected and then examined under light microscope using stereological and histopathological methods. Stereological findings showed that the total number of Purkinje cells and granular cells were significantly decreased in the SK group than the control group (p < 0.05). In addition, the mean volumes of molecular layer, granular layer, white matter, and cerebellum were significantly decreased in the SK group compared to the control group (p < 0.05). In the SK + GB group, the total number Purkinje cell, and granular cells, as well as the mean volumes of molecular layer, granular layer, white matter, and cerebellum were significantly increased than the SK group (p < 0.05). Histopathological evaluation also confirmed our stereological findings in the cerebellar tissues. Our results showed that prenatal exposure to SK caused significant changes in the cerebellar architectures of rats, and that GB administration significantly attenuated the deleterious effect of SK on the cerebellar tissues.

Extracellular vesicles derived from dental mesenchymal stem/stromal cells with gemcitabine as a cargo have an inhibitory effect on the growth of pancreatic carcinoma cell lines in vitro

Extracellular vesicles (EVs) are nowadays a target of interest in cancer therapy as a successful drug delivering tool. Based on their many beneficial biocompatible properties are designed to transport nucleic acids, proteins, various nanomaterials or chemotherapeutics. Extracellular vesicles derived from mesenchymal stem/stromal cells (MSCs) possess their tumor-homing abilities. This inspired us to engineer the MSC's EVs to be packed with chemotherapeutic agents and deliver it as a Trojan horse directly into tumor cells. In our study, human dental pulp MSCs (DP-MSCs) were cultivated with gemcitabine (GCB), which led to its absorption by the cells and subsequent secretion of the drug out into conditioned media in EVs. Concentrated conditioned media containing small EVs (potentially exosomes) significantly inhibited the cell growth of pancreatic carcinoma cell lines in vitro. DP-MSCs were simultaneously engineered to express a suicide gene fused yeast cytosinedeaminase:uracilphosphoribosyltransferase (yCD::UPRT). The product of the suicide gene converts non-toxic prodrug 5-fluorocytosine (5-FC) to highly cytotoxic chemotherapeutic drug 5-fluorouracil (5-FU) in the recipient cancer cells. Conversion of 5-FC to 5-FU had an additional effect on cancer cell's growth inhibition. Our results showed a therapeutic potential for DP-MSC-EVs to be designed for successful delivering of chemotherapeutic drugs, together with prodrug suicide gene therapy system.

Muehrcke’s Lines in a Known Case of Lung Carcinoma on Chemotherapy

Muehrcke’s nails are changes in the fingernail that may be a sign of an underlying medical condition. These lines have been linked to low levels of albumin, indicating decreased protein synthesis as a result of liver disease, nephrotic syndrome, glomerulonephritis, malnutrition, or dietary protein deficiency. It can also occur during periods of metabolic stress such as systemic infection, trauma, Acquired immunodeficiency syndrome, chemotherapy drugs, Hodgkin’s disease, pellagra, and sickle cell anemia. Muehrcke’s nails are characterized by double white transverse line, across the nail, parallel to the lunula on the fingernails, and thumb involvement is rare. Treatment is the correction of albumin deficiency or any other underlying conditions. Examination of the nails should be an integral part of a complete dermatological examination. Here, we report a case of 47-year-old male diagnosed with Muerhcke’s lines, secondary to intake of cytotoxic chemotherapeutic drugs.

Brain Protection by Methylene Blue and Its Derivative, Azur B, via Activation of the Nrf2/ARE Pathway in Cisplatin-Induced Cognitive Impairment.

Cisplatin is a cytotoxic chemotherapeutic drug that leads to DNA damage and is used in the treatment of various types of tumors. However, cisplatin has several serious adverse effects, such as deterioration in cognitive ability. The aim of our work was to study neuroprotectors capable of preventing cisplatin-induced neurotoxicity. Methylene blue (MB) and AzurB (AzB) are able to neutralize the neurotoxicity caused by cisplatin by protecting nerve cells as a result of the activation of the Ntf2 signaling pathway. We have shown that cisplatin impairs learning in the Morris water maze. This is due to an increase in the amount of mtDNA damage, a decrease in the expression of most antioxidant genes, the main determinant of the induction of which is the Nrf2/ARE signaling pathway, and genes involved in mitophagy regulation in the cortex. The expression of genes involved in long-term potentiation was suppressed in the hippocampus of cisplatin-injected mice. MB in most cases prevented cisplatin-induced impairment of learning and decrease of gene expression in the cortex. AzB prevented the cisplatin-induced decrease of genes in the hippocampus. Also, cisplatin induced disbalance in the gut microbiome, decreased levels of Actinotalea and Prevotella, and increased levels of Streptococcus and Veillonella. MB and AzB also prevented cisplatin-induced changes in the bacterial composition of the gut microbiome.

Tisotumab vedotin for the treatment of cervical carcinoma.

Cervical cancer is one of the most common gynecological malignancies. At present, cytotoxic chemotherapeutic drugs and immunotherapy are the main therapeutic options for recurrent and metastatic cervical cancer. Tisotumab vedotin is an antibody-drug conjugate (ADC) and a potential novel treatment for cervical carcinoma. Tisotumab vedotin targets tissue factor (TF), which is highly expressed on the surface of cervical cancer cells, by delivering the cytotoxic agent monomethyl auristatin E (MMAE) directly into tumor cells. Currently, the U.S. Food and Drug Administration (FDA) has approved tisotumab vedotin for the treatment of adult female patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. This article reviews the results of preclinical studies and clinical trials of tisotumab vedotin. The findings suggest that tisotumab vedotin can induce clinically significant and long-lasting remission with controllable and tolerable safety in the difficult-to-treat group of cervical cancer patients.

Brain metastasis: Recent treatment modalities and future-perspectives.

With the advent of novel systemic therapies, such as molecular targeted therapy and immune checkpoint inhibitors, the treatment of advanced-stage cancer is markedly transitioning. The treatment for brain metastasis is influenced by these new therapies. Moreover, the frequency of brain metastasis is associated with cancer genetics. Since conventional cytotoxic chemotherapeutic drugs cannot easily cross the brain-blood barrier, radiotherapy plays a major role in the management of brain metastasis. Whole-brain radiotherapy (WBRT) has been frequently used, especially for multiple metastatic brain tumors; however, late adverse effects on cognitive function are a significant clinical problem of WBRT in patients with an otherwise good prognosis and overall survival rate. Some novel systemic agents are effective against brain metastasis. Moreover, advances in radiotherapy technology have made it possible to deliver optimal radiation doses to patients with brain metastasis, with fewer adverse events. Brain metastasis has a significant impact on the quality of life of patients with advanced-stage cancer; therefore, its appropriate management is an important factor in the comprehensive treatment of cancer.

Blockade of ALDH in Cisplatin-Resistant Ovarian Cancer Stem Cells In Vitro Synergistically Enhances Chemotherapy-Induced Cell Death.

Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer-related death. The high mortality and morbidity associated with EOC are mostly due to late diagnosis and chemotherapy drug resistance. Currently, the standard first-line chemotherapy regimen is systemic administration of platinum-based chemotherapy combined with a taxane. A major problem besides cisplatin resistance (occurring in nearly one-third of patients) is the greater toxicity of the drug combinations. A synergistic treatment with drug supporting activity could maximize the cytotoxic effects of chemotherapeutic agents on tumor cells while decreasing the dosage of each drug to potentially reduce toxicity. The ALDH-blocking agent Disulfiram (DSF), a clinically approved drug used for alcoholism treatment, has displayed promising anti-cancer activity. We previously described that blocking ALDH activity enhances the induction of apoptosis, especially in ovarian cancer stem cells treated with chemotherapeutic agents. In this study, we further investigated the synergistic effect of DSF in combination with cytotoxic chemotherapeutic drugs. The concentration of each chemotherapeutic agent could be significantly reduced with sustained efficacy on tumor cell apoptosis in cell lines in vitro (Dose-Reduction Index at IC50 from 1 to 50). Moreover, the potential chemo-sensitizing effects of DSF on ALDH-associated cisplatin-resistant ovarian cancer stem cells were also investigated and shown that in contrast to its high resistance to cisplatin, the cisplatin-resistant cells remain very sensitive to DSF-induced cytotoxicity (apoptosis and necrosis: cisplatin-resistant cells vs. parental cells: 60.4% vs. 20.5%). In combination with DSF and cisplatin, relatively more apoptosis and necrosis were induced in cisplatin-resistant cells than in their parental cells (apoptosis and necrosis: cisplatin-resistant cells vs. parental cells: 81.5% vs. 50.1%). A transcriptome analysis identified that ALDH was mainly enriched in the cancer-associated fibroblasts and showed that ALDH plays roles in responding to oxidative stress, metabolisms, and energy transition in the ALDH-associated cisplatin-resistant ovarian cancer stem cells. In conclusion, our data demonstrate a key role of ALDH-associated cisplatin-resistant cancer stem cells and identifies DSF as a potential adjuvant for a rational protocol design by computational quantitative assessment in vitro on ovarian cancer cell lines. Our work contributes to resolving the ALDH-associated cisplatin resistance and provides a resource for the development of novel chemotherapeutic regimens.

Hydrazone modified nanoscale metal-organic frameworks as pH responsive nanoplatforms for cancer therapy

Practical clinical applications of chemotherapeutic drug are limited due to inevitable drawbacks such as low water solubility, big side effect and poor therapeutic efficiency. To overcome these drawbacks, we developed a novel nanoscale metal-organic framework (nMOFs)-based pH-responsive drug delivery system designed for efficient cancer therapy. In this work, a zirconium-based nMOFs UiO-66 was synthesized, and its surface was engineered to convert partial amino groups to hydrazone groups through stepwise organic transformations. Subsequently, the anticancer agent doxorubicin (DOX) served as a therapeutic drug and a fluorescent label was loaded through acid-labile hydrazone linkage to yield UiO-66-DOX. Acidic pH conditions (such as those surrounding tumor cells) catalyzed the hydrolysis of the hydrazone linkage and promoted the DOX release. These novel pH-sensitive drug delivery system will help to achieve safe delivery of the very cytotoxic chemotherapeutic drug (such as DOX), allowing to reduce the therapeutic dose and minimizing drug secondary effects.

Antibody-Drug Conjugates Targeting the Human Epidermal Growth Factor Receptor Family in Cancers.

Members of the human epidermal growth factor receptor (HER) family, which includes HER1 (also known as EGFR), HER2, HER3 and HER4, have played a central role in regulating cell proliferation, survival, differentiation and migration. The overexpression of the HER family has been recognized as one of the most common cellular dysregulation associated with a wide variety of tumor types. Antibody-drug conjugates (ADCs) represent a new and promising class of anticancer therapeutics that combine the cancer specificity of antibodies with cytotoxicity of chemotherapeutic drugs. Two HER2-directed ADCs, trastuzumane-emtansine (T-DM1) and trastuzumab-deruxtecan (DS-8201a), have been approved for HER2-positive metastatic breast cancer by the U.S. Food and Drug Administration (FDA) in 2013 and 2019, respectively. A third HER2-directed ADC, disitamab vedotin (RC48), has been approved for locally advanced or metastatic gastric or gastroesophageal junction cancer by the NMPA (National Medical Products Administration) of China in 2021. A total of 11 ADCs that target HER family receptors (EGFR, HER2 or HER3) are currently under clinical trials. In this review article, we summarize the three approved ADCs (T-DM1, DS-8201a and RC48), together with the investigational EGFR-directed ADCs (ABT-414, MRG003 and M1231), HER2-directed ADCs (SYD985, ARX-788, A166, MRG002, ALT-P7, GQ1001 and SBT6050) and HER3-directed ADC (U3-1402). Lastly, we discuss the major challenges associated with the development of ADCs, and highlight the possible future directions to tackle these challenges.

Prevention of doxorubicin-induced experimental cardiotoxicity by Nigella sativa in rats

IntroductionDoxorubicin (DOX) is an anthracycline cytotoxic chemotherapeutic drug that is commonly used in cancer treatment. A major side effect limiting the clinical use of DOX is cardiotoxicity due to oxidative injury. Nigella sativa (NS) is an annual flowering plant with antioxidant properties. Its seeds contain several bioactive constituents such as saturated and unsaturated fatty acids, thymoquinone, dithymoquinone, thymohydroquinone, and thymol. In this study, we investigated the effect of NS extract on DOX-induced cardiotoxicity. MethodsThe experimental study animals consisted of 28 male Sprague Dawley rats weighing between 300 and 400 g. Four study groups each of seven rats were defined: controls; NS extract; DOX; and DOX+NS. Control and DOX rats received standard food, while each rat in the NS and DOX+NS groups also received 100 mg/kg NS extract orally. At day 28 of follow-up, rats in the DOX groups were administered a single 10 mg/kg intraperitoneal dose of DOX, while rats in the control and NS groups received a single 10 mg/kg dose of physiological saline solution. All animals were monitored for 35 days. On day 35, the rats were decapitated and serum and cardiac tissue samples were obtained. Troponin and NT-proBNP levels were measured in blood sera, while malondialdehyde (MDA), nitric oxide, total antioxidant capacity (TAC), and total oxidative stress (TOS) levels were quantified in sera and tissue samples. Histological alterations that were assessed in cardiac tissue included myocyte disarray, small vessel disease, myocyte hypertrophy, and fibrosis. ResultsThe DOX group had significantly higher NT-proBNP, TOS, and MDA, with greater histopathological derangement. TAC was significantly elevated in the DOX+NS group, which also exhibited significantly lower troponin, TOS, and MDA, as well as significantly higher TAC compared to the DOX group. Histopathological examination showed that the significant structural derangement observed in DOX rats was markedly and significantly reduced in DOX+NS rats. ConclusionOur results suggest that NS extract may prevent DOX-induced cardiotoxicity and thus represents a promising cardioprotective agent.

Harnessing Natural Products of Marine Origin for Induction of Immunogenic Cell Death

Conventional cancer chemotherapy aims to kill highly proliferating tumor cells and is often immunosuppressive due to its off-target side effects. However, certain cytotoxic cancer chemotherapeutic drugs can kill tumor cells by triggering immunogenic cell death (ICD). Cells undergoing ICD release damage-associated molecular patterns (DAMPs) to activate robust innate and adaptive anti-tumor immune responses. Despite many compounds being able to trigger one or two hallmarks of ICD, very few bona fide ICD inducers are available. Identification of bioactive natural ICD inducers with low side effects and high tolerability represents a priority in biomedical research. In this review, we discuss the various strategies to regulate the hallmarks of ICD and enhance immunogenic potentials. We focus on evaluating the potential of natural compounds of marine origin to amplify the effects of ICD and therefore serve as novel therapeutic anti-cancer agents alone or in combination with existent chemo- or immune-therapies.

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.