Cytotoxic Chemotherapeutic Agents Research Articles

Effects of temozolomide on tumor mutation burden and microsatellite instability in melanoma cells.

The efficacy of combination therapy with an immune checkpoint inhibitor (ICI) and cytotoxic chemotherapeutic agents has been investigated in cancer, including melanoma. Before ICIs were introduced, dacarbazine or temozolomide (TMZ) were used to treat melanoma. Several studies using glioma or colorectal cancer cells showed that TMZ can increase the tumor mutation burden (TMB) and induce mismatch repair (MMR) deficiency associated with microsatellite instability (MSI). These could increase immunoreactivity to an ICI, but this has not been evaluated in melanoma cells. We investigated the effects of TMZ on MSI status and TMB in melanoma cells. To evaluate the TMB, we performed whole-exome sequencing using genomic DNA from the human melanoma cell lines Mel18, A375, WM266-4, G361, and TXM18 before and after TMZ treatment. Polymerase chain reaction amplification of five mononucleotide repeat markers, BAT25, BAT26, NR21, NR24, and MONO27, was performed, and we analyzed changes in the MSI status. In all cell lines, the TMB was increased after TMZ treatment (the change amount of TMB with ≤ 5% variant allele frequency [VAF] was 18.0-38.3 mutations per megabase) even in the condition without obvious cytological damage. MSI after TMZ treatment was not observed in any cells. TMZ increased TMB but did not change MSI status in melanoma cells.

Epidemiological and therapeutic profiles of lung cancer patients in the Hokushin Region Japan: a retrospective hospital administrative database study

ObjectiveThis study was performed to validate the epidemiology, initial treatment, and clinical practice of lung cancer patients in the Hokushin region, Japan.MethodsWe retrospectively surveyed data of 5503 newly diagnosed and registered lung cancer patients in 22 principal hospital-based cancer registries in Hokushin region linked with health insurance claims data for registered patients between 2016 and 2017.ResultsThe patients consisted of 3677 (66.8%) men and 1826 (33.2%) women with a mean (range) age of 72.2 (27–103) years). Diagnoses were small cell lung cancer (n = 512, 9.4%), squamous cell carcinoma (n = 1083, 19.7%), and non-squamous non-small cell lung cancer (NSCLC; n = 3906, 70.9%). The population with stage I disease in Toyama prefecture (41.1%) was smaller than in the other three prefectures associated with reduced selection of initial surgical therapy and increased frequencies of stage IV disease (33.2%) and best supportive care (18.6%). Initial chemotherapy for stage IV non-squamous NSCLC consisted of tyrosine kinase inhibitors in 39.3% of cases for EGFR and 4% of cases for ALK-positive non-squamous NSCLC, followed by platinum compounds (25.9%) non-platinum compounds (12.9%), and immune checkpoint inhibitors (10.2%). Carboplatin was the commonly prescribed first-line cytotoxic chemotherapeutic agent (65.4% of patients under 75 years and in 96.7% of patients over 75 years).ConclusionThis study revealed real-world data on epidemiological and treatment status in lung cancer in four prefectures in Hokushin region, Japan. Simultaneous analysis of nationwide registry and insurance data could provide valuable insights for the development of lung cancer screening and medical treatment strategies. In addition, the comparative data analysis with other lesions or countries will be useful for evaluating the differences in clinical practice of cancer managements.

Effect of whole-brain radiotherapy with platinum-based chemotherapy in non-small cell lung cancer patients with multiple metastases including brain metastases

Current guidelines recommend that cytotoxic chemotherapy be considered first in non-small cell lung cancer (NSCLC) patients with multiple metastases, and whole-brain radiotherapy (WBRT) is not initially recommended even if brain metastases are present. However, cytotoxic chemotherapeutic agents are less effective in brain metastases due to poor blood–brain barrier permeability. We investigated the effect of WBRT in combination with cytotoxic chemotherapy on survival in NSCLC patients who were EGFR, ALK, and PD-L1 negative, had an ECOG PS of 2, and had multiple metastases including brain metastases. From January 2005 to December 2018, histologically confirmed NSCLC patients who were EGFR, ALK, and PD-L1 negative, had an ECOG PS of 2, and had multiple metastases including brain metastases were included in this study. Patients were classified into two groups based on receiving WBRT prior to or concurrently with administration of first-line chemotherapeutic agents or receiving chemotherapy only. We compared intracranial progression-free survival (iPFS) and overall survival (OS). Of the 240 NSCLC patients with brain metastases at diagnosis and an ECOG PS of 2, 67 patients were EGFR, ALK, and PD-L1 negative with multiple metastases including brain metastases. Among those patients, 43 (64.2%) received WBRT prior to or concurrently with platinum-based chemotherapy. Patients who received WBRT prior to or concurrently with chemotherapy had better iPFS (7.7 months [4.8–10.6] vs. 3.5 months [2.1–4.9], p = 0.009) and OS (10.8 months [5.9–15.7] vs. 6.1 months [1.9–10.3], p = 0.038) than those who did not receive WBRT. In multivariate analyses, WBRT was significantly associated with iPFS (HR: 1.94 and 95% CI 1.11–3.40, p = 0.020) and OS (HR: 1.92 and 95% CI 1.08–3.42, p = 0.027). In NSCLC patients who are EGFR, ALK, and PD-L1 negative, have an ECOG PS of 2, and have multiple metastases including brain metastases, WBRT prior to or concurrently with chemotherapy could improve iPFS and OS. Therefore, the combination of WBRT with cytotoxic chemotherapy should be considered in these patients.

Natural products as drug candidates for breast cancer (Review).

Progression of early-stage breast cancer to advanced-stage metastatic disease represents a major cause of death in women. Long-term conventional and targeted therapy for breast cancer includes multi-drug combinations of cytotoxic chemotherapeutics and pathway-selective small molecule inhibitors. These treatment options are frequently associated with systemic toxicity, intrinsic/acquired therapy resistance and emergence of a drug-resistant cancer stem cell population. This stem cell population has a chemo-resistant, cancer-initiating, premalignant phenotype that is accompanied by cellular plasticity and metastatic potential. These limitations emphasize an unmet need to identify testable alternatives against therapy-resistant metastatic breast cancer. Natural products such as dietary phytochemicals, nutritional herbs and their constitutive bioactive agents have documented human consumption, and lack detectable systemic toxicity and resultant off-target unfavorable side effects. Because of these advantages, natural products may represent testable alternatives for therapy-resistant breast cancer. The present review discusses published evidence for growth inhibitory efficacy of natural products on cellular models for molecular subtypes of clinical breast cancer and development of drug-resistant stem cell models. Collectively, this evidence validates mechanism-based experimental approaches to screen and prioritize efficacious bioactive agents from natural products as novel drug candidates that may function as therapeutic alternatives for breast cancer.

Current Bioanalysis of Molecularly Targeted Drugs Using Liquid Chromatography–Tandem Mass Spectrometry

Molecular targeted drugs (MTDs), such as tyrosine kinase inhibitors, have been actively developed and widely used in recent years due to their high selectivity and therapeutic efficacy compared to conventional cytotoxic chemotherapeutic agents. Bioanalysis of MTDs for therapeutic drug monitoring (TDM) is performed by many medical and clinical laboratories, and the implementation of TDM for MTDs can lead to better control of tumor progression, reduce tumor recurrence, and minimize side effects. Since bioanalysis of MTDs often requires high detection sensitivity with a limit of quantitation of 1 ng/mL or less, many of the reported analytical methods are performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). This review highlights recent bioanalytical methods for MTDs using LC-MS/MS. We selected articles on bioanalysis of MTDs of signal transduction inhibitors that (1) were published after 2017, (2) used human samples (whole blood, plasma, serum, urine), and (3) underwent analytical validation. Typical analytical conditions, notable pretreatment techniques, LC separations, and measurement techniques are outlined.

Protective Effects of Momordica charantia (Bitter Melon) against Methotrexate- induced Kidney Damage

Background: Methotrexate is a cytotoxic chemotherapeutic agent that has severe side effects, such as nephrotoxicity. Momordica charantia is a bright yellow-orange fruity plant that has been shown to have antioxidant, antidiabetic, and anti-inflammatory properties. Objective: This study scrutinized the protective effects of Momordica charantia extract against methotrexate- induced nephrotoxicity. Methods: 24 Sprague Dawley male rats were divided into three experimental groups (8 rats in each): Control (C); Methotrexate (MTX); and Methotrexate plus Momordica charantia (MTX+MC). All rats were fed ad libitum and tap water. Methotrexate was administered at 20 mg/kg intraperitoneally as a single dose. In the MTX+MC group, MC was administered at a dose of 50mg/kg for 5 days orally. At the end of the 5th day, the rats were decapitated and kidney samples were taken to analyze glutathione (GSH), malondialdehyde (MDA), myeloperoxidase (MPO), 8-hydroxy-2'-deoxyguanosine (8-OHdG) and caspase-3 activity. Data was analyzed with GraphPad Prism 5.0. Results: Findings showed that while there was a significant increase in MDA, MPO, 8-OHdG levels, and an essential reduction in GSH levels in the MTX-treated group when compared with the control group, bitter melon treatment significantly reversed MDA, MPO, and 8-OHdG levels (p< 0.001). GSH level elevation was observed in the MTX-MC group when compared to the MTX-treated group (p< 0.001). Conclusion: This study showed that bitter melon is thought to have a protective effect against kidney damage caused by methotrexate. With future studies, we believe that the use of bitter melon extract as a protective agent in kidney damage caused by drug-induced oxidative damage will bring an innovative approach to treatment.

Seamless phaseII/III design: a useful strategy to reduce the sample size for dose optimization.

The traditional more-is-better dose selection paradigm, originally developed for cytotoxic chemotherapeutics, can be problematic when applied to the development of novel molecularly targeted agents. Recognizing this issue, the US Food and Drug Administration initiated Project Optimus to reform the dose optimization and selection paradigm in oncology drug development, emphasizing the need for greater attention to benefit-risk considerations. We identify different types of phase II/III dose-optimization designs, classified according to trial objectives and endpoint types. Through computer simulations, we examine their operating characteristics and discuss the relevant statistical and design considerations for effective dose optimization. Phase II/III dose-optimization designs are capable of controlling family-wise type I error rates and achieving appropriate statistical power with substantially smaller sample sizes than the conventional approach while also reducing the number of patients who experience toxicity. Depending on the design and scenario, the sample size savings range from 16.6% to 27.3%, with a mean savings of 22.1%. Phase II/III dose-optimization designs offer an efficient way to reduce sample sizes for dose optimization and accelerate the development of targeted agents. However, because of interim dose selection, the phase II/III dose-optimization design presents logistical and operational challenges and requires careful planning and implementation to ensure trial integrity.

Pharmacological impact of microRNAs in head and neck squamous cell carcinoma: Prevailing insights on molecular pathways, diagnosis, and nanomedicine treatment.

Head and neck squamous cell carcinoma is a disease that most commonly produce tumours from the lining of the epithelial cells of the lips, larynx, nasopharynx, mouth, or oro-pharynx. It is one of the most deadly forms of cancer. About one to two percent of all neo-plasm-related deaths are attributed to head and neck squamous cell carcinoma, which is responsible for about six percent of all cancers. MicroRNAs play a critical role in cell proliferation, differentiation, tumorigenesis, stress response, triggering apoptosis, and other physiological process. MicroRNAs regulate gene expression and provide new diagnostic, prognostic, and therapeutic options for head and neck squamous cell carcinoma. In this work, the role of molecular signaling pathways related to head and neck squamous cell carcinoma is emphasized. We also provide an overview of MicroRNA downregulation and overexpression and its role as a diagnostic and prognostic marker in head and neck squamous cell carcinoma. In recent years, MicroRNA nano-based therapies for head and neck squamous cell carcinoma have been explored. In addition, nanotechnology-based alternatives have been discussed as a promising strategy in exploring therapeutic paradigms aimed at improving the efficacy of conventional cytotoxic chemotherapeutic agents against head and neck squamous cell carcinoma and attenuating their cytotoxicity. This article also provides information on ongoing and recently completed clinical trials for therapies based on nanotechnology.

Abstract 4886: PARP-1 and γ-GCS inhibitors enhance platinum sensitivity in ovarian cancer

Abstract Background: Ovarian cancer is the most important cause of gynaecological cancer-related mortality globally. Approximately 80% of patients are diagnosed with advanced stage (FIGO stage III-IV) of ovarian cancer. The standard treatment approach for advanced EOC is primary debulking surgery followed by adjuvant chemotherapy using taxanes plus platinum. Resistance to platinum based chemo remains a key reason for treatment failure in advanced epithelial ovarian cancer (EOC). Therapeutic efficacy of Poly [ADP-ribose] polymerase 1 (PARP1) and Gamma-glutamyl cysteine Synthetase (γ-GCS)inhibitors in ovarian cancer remains undefined, either as a single agent or in combination with cisplatin. Material and Methods: We determined the combined effect of PJ34 (PARP1 inhibitor) and BSO (Buthionine-sulfoximine- (γ-GCS inhibitor) with cisplatin in ovarian cancer cell lines (OVSAHO, KURAMOCHI, and IGROV1) by MTT assay. PARP1 and GCS levels were analyzed by western blotting. We employed flow cytometry for cell cycle analysis as well as for apoptosis studies. Analysis was done using Graph Pad Prism-6. Results were considered to be statistically significant when p value was < 0.05. Results and Conclusion: Combination of cisplatin with PJ34 and BSO augmented cisplatin toxicity in vitro by decreasing cell proliferation and enhancing cell cycle block and cell death when compared with either single agent. A significant cell death (p= <0.05) was observed with the combination of cisplatin, BSO and PJ34. Conclusion: In conclusion, our study provide experimental evidence on the combined effect of PARP-1 and GCS inhibition on CDDP-induced cytotoxicity in epithelial ovarian cancer cells. We propose that PARP-1and BSO inhibitors can be combined with cytotoxic chemotherapeutic agents such as CDDP to enhance the cytotoxicity of chemotherapeutic agents and inhibit key signalling pathways involved in cell proliferation and apoptosis. Future comprehensive studies are needed to demonstrate further validation of above combination. Keywords: Ovarian Cancer, cisplatin, PARP-1, PJ34, γ -GCS, β-actin, Glutathione. Abbreviations: Epithelial Ovarian Cancer (EOC), cisplatin (CDDP), Glutathione (GSH), Gamma Glutamyl Cysteine Synthetase (γ-GCS), Poly (ADP ribosyl) polymerase-1 (PARP1), Nucleotide excision repair (NER),homologous repair (HR), Enzyme-linked immunosorbent assay (ELISA), Buthionine Sulfoximine (BSO), Quantitative Polymerase Chain Reaction (qPCR), Peripheral Blood (PB). Propidium Iodide(PI). Citation Format: Luxmi Devi, Ashok Sharma, Lalit Kumar. PARP-1 and γ-GCS inhibitors enhance platinum sensitivity in ovarian cancer. [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 4886.

Abstract 6252: HDAC inhibition increases Ewing sarcoma sensitivity to chemotherapy

Abstract Purpose: The survival rate of those with Ewing sarcoma (ES) has seen very little improvement over the past several decades and remains dismal for those with recurrent or metastatic disease. Current treatment for Ewing sarcoma includes a combination of cytotoxic chemotherapeutic agents and local control with radiation and/or surgery. The purpose of this study is to identify currently available targeted agents which may be combined with chemotherapy for use in Ewing sarcoma to improve patient outcomes. Methods: Novel targeted approaches for the treatment of ES were identified using RNA sequencing performed on ES patient tumors with bioinformatic analysis of gene expression. HDAC inhibitors were tested on patient cell lines at escalating doses and cell viability was assessed with CellTiter-Glo 2.0 and analyzed with GraphPad Prism to determine the IC50. Cells were treated with Panobinostat for 12 and 24 hours and RNA sequencing was performed. Cell cycle analysis was performed using Incucyte® Cell Cycle Lentivirus Reagent and analyzed using an Incucyte® S3. At 24- and 48-hours western blot analysis was performed to evaluate the effect on cell cycle and apoptosis. Combination studies with standard chemotherapy were performed and viability was assessed with CellTiter-Glo 2.0. At 24 hours of treatment with a combination of doxorubicin and HDAC inhibition western blot analysis was performed to evaluate changes in DNA damage and repair. Results: RNA analysis identified HDAC2 as a potential therapeutic target. The pan-HDAC inhibitors, Panobinostat and Belinostat, and the HDAC1/2 inhibitor, Romidepsin, were cytotoxic to all Ewing sarcoma cell lines tested with clinically relevant IC50s. Mechanistically, pathways involved in cell cycle progression and DNA repair were repressed by Panobinostat as shown by RNA sequencing and western blotting (Cyclin D1, pRb, CHK1). Additionally, cell cycle analysis has shown a G1 arrest in response to HDAC inhibition. HDAC inhibitors significantly decrease cell viability when combined with standard chemotherapy (upfront and relapse therapy) compared to that of chemotherapy alone. When combined with doxorubicin, CHK1 and CHK2 were significantly decreased and pH2AX was significantly increased indicating an accumulation of DNA damage. Conclusion: This work highlights that combining HDAC inhibitors with standard of care chemotherapy may be an effective treatment and improve outcomes for Ewing sarcoma patients. Future studies of HDAC inhibitors combined with chemotherapy drugs will aim to determine efficacy in xenograft models. Citation Format: Kaitlyn H. Smith, Chloe Sholler, Divya Gandra, Kimberly McKinney, Karl Dykema, Abhinav Nagulapally, Erin Trovillion. HDAC inhibition increases Ewing sarcoma sensitivity to chemotherapy [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 6252.

Circ_0001312 Silencing Suppresses Doxorubicin-Induced Cardiotoxicity via MiR-409-3p/HMGB1 Axis.

Doxorubicin (DOX) is a potent cytotoxic chemotherapeutic agent limited in clinical application owing to its cumulative and irreversible cardiotoxicity. Circ_0001312 is highly expressed in patients with heart failure. However, it is still unclear whether circ_0001312 plays any roles in DOX-induced cardiotoxicity.Human AC16 cardiomyocytes in functional group were stimulated with DOX. The levels of genes and proteins were detected by qRT-PCR and western blotting. The proliferation, apoptosis, as well as inflammatory and oxidative injury in cardiomyocytes were investigated. Dual-luciferase reporter, RNA immunoprecipitation, and pull-down assays were utilized to confirm the binding between miR-409-3p and circ_0001312 or HMGB1 (high-mobility group box 1). Exosomes were isolated by using the commercial kit and identified by transmission electron microscopy (TEM) and nanoparticle-tracking analysis (NTA).DOX impaired cardiomyocyte proliferation and induced apoptotic, inflammatory, and oxidative injury in cells. Furthermore, it promoted circ_0001312 expression, and the knockdown of circ_0001312 could reverse DOX-evoked cardiomyocyte injury. In terms of mechanics, circ_0001312 bound competitively to miR-409-3p to up-regulate HMGB1, which was a target of miR-409-3p. DOX decreased the miR-409-3p but increased the HMGB1 expression in cardiomyocytes. Functionally, miR-409-3p inhibition attenuated the protective action of circ_0001312 silencing on cardiomyocytes under DOX treatment. Moreover, miR-409-3p could abate DOX-evoked apoptosis, and inflammation and oxidative stress in cardiomyocytes, and these effects were counteracted by HMGB1 overexpression. In addition, circ_0001312 was secreted by exosomes and could be transmitted via exosomes.Circ_0001312 reversed the cytotoxic effects mediated by DOX on cardiomyocytes via the miR-409-3p/HMGB1 axis. Besides, it was released to the extracellular space by exosomes.

Glioblastoma-Derived Small Extracellular Vesicles: Nanoparticles for Glioma Treatment

Glioblastoma (GBM), characterized by fast growth and invasion into adjacent tissue, is the most aggressive cancer of brain origin. Current protocols, which include cytotoxic chemotherapeutic agents, effectively treat localized disease; however, these aggressive therapies present side effects due to the high doses administered. Therefore, more efficient ways of drug delivery have been studied to reduce the therapeutic exposure of the patients. We have isolated and fully characterized small extracellular vesicles (EVs) from seven patient-derived GBM cell lines. After loading them with two different drugs, Temozolomide (TMZ) and EPZ015666, we observed a reduction in the total amount of drugs needed to trigger an effect on tumor cells. Moreover, we observed that GBM-derived small EVs, although with lower target specificity, can induce an effect on pancreatic cancer cell death. These results suggest that GBM-derived small EVs represent a promising drug delivery tool for further preclinical studies and potentially for the clinical development of GBM treatments.

Paraoxonase-2 is upregulated in triple negative breast cancer and contributes to tumor progression and chemoresistance.

Triple negative breast cancer (TNBC) displays a high aggressive behavior, tendency to relapse and early metastasize, leading to poor prognosis. The lack of estrogen receptors, and human epidermal growth factor receptor 2, prevents the use of endocrine or molecular targeted therapy, being therapeutical options for TNBC managements mostly limited to surgery, radiotherapy and mainly chemotherapy. While an important number of TNBCs initially responds to chemotherapy, they are prone to develop chemoresistance over the time. Thus, there is an urgent need to identify novel molecular targets to improve the outcome of chemotherapy in TNBC. In this work we focused on the enzyme paraoxonase-2 (PON2) which has been reported to be overexpressed in several tumors contributing to cancer aggressiveness and chemoresistance. Through a case-control study, we analyzed PON2 immunohistochemical expression in breast cancer molecular subtypes Luminal A, Luminal B, Luminal B HER2+, HER2 + and TNBC. Subsequently, we evaluated the in vitro effect of PON2 downregulation on cell proliferation and response to chemotherapeutics. Our results showed that the PON2 expression levels were significantly upregulated in the infiltrating tumors related to the subtypes Luminal A, HER2+ and TNBC compared to the healthy tissue. Furthermore, PON2 downregulation led to a decrease in cell proliferation of breast cancer cells, and significantly enhanced the cytotoxicity of chemotherapeutics on the TNBC cells. Although further analyses are necessary to deeply understand the mechanisms by which the enzyme could participate to breast cancer tumorigenesis, our results seem to demonstrate that PON2 could represent a promising molecular target for TNBC treatment.

Protective effects of sitagliptin on methotrexate-induced nephrotoxicity in rats

Methotrexate (MTX), a cytotoxic chemotherapeutic and immunosuppressant agent, is widely used in the treatment of autoimmune diseases and different types of cancers. However, its use has been limited by its life-threatening side effects, including nephrotoxicity and hepatotoxicity. The purpose of this study was to investigate the protective effect of sitagliptin on methotrexate (MTX)-induced nephrotoxicity in rats. Twenty-four rats were divided into four groups: control group, which received the vehicle for 6 days; MTX group, which received a single dose of MTX, followed by five daily doses of vehicle dosing; MTX + sitagliptin group, which received a single dose of MTX 1 h after the first sitagliptin treatment and six daily doses of sitagliptin; and sitagliptin group, which received sitagliptin for 6 days. Both MTX and sitagliptin were given as intraperitoneal injections at a dose of 20 mg/kg body weight. All rats were euthanized on the seventh day of the study. Kidney tissues were harvested and blood samples were collected. Serum levels of blood urea nitrogen (BUN) and creatinine were evaluated. Furthermore, catalase, glutathione peroxidase, superoxide dismutase activities, and malondialdehyde (MDA) levels were determined in kidney tissue. In addition, histopathological analysis was conducted. Histopathological evaluation showed that MTX-induced marked kidney injury. Biochemical analysis revealed a significant increase of BUN and creatinine in the serum of the MTX group. Furthermore, oxidative stress and depressed antioxidant system of the kidney tissues were evident in the MTX group. Sitagliptin did not affect these endpoints when administered alone, but it significantly attenuated the observed MTX-induced effects. These results suggest that sitagliptin exhibits potent anti-oxidant properties against the nephrotoxicity induced by MTX in rats.

Immune checkpoint inhibitors modulate the cytotoxic effect of chemotherapy in lung adenocarcinoma cells.

Immunotherapy using immune checkpoint inhibitors (ICIs) has significantly improved survival in patients with non-small cell lung cancer (NSCLC), and ICIs are increasingly used in combination with cytotoxic treatments, such as chemotherapy. Although combined treatments are more effective, not all patients respond to the therapy; therefore, a detailed understanding of the effect of treatment combinations at the tumour level is needed. The present study aimed to explore whether ICIs could affect the cytotoxic effects of chemotherapy on lung adenocarcinoma cell lines with different PD-L1 expression levels (high, HCC-44; low, A-549). Using the resazurin-based assay, the efficacy of seven chemotherapeutic agents (cisplatin, etoposide, gemcitabine, pemetrexed, vinorelbine, docetaxel and paclitaxel) was compared in the presence or absence of the individually chosen single doses of four ICIs (nivolumab, pembrolizumab, atezolizumab and durvalumab). The results revealed that different ICIs can exhibit either potentiating or depotentiating effects, depending on the chemotherapy agent or lung adenocarcinoma cell line used. Durvalumab was the most promising ICI, which potentiated most chemotherapy agents in both cell lines, especially in the case of high PD-L1 expression. By contrast, nivolumab, exhibited depotentiating trends in several combinations. The immunostaining of γH2AX in treated cells confirmed that the potentiation of the chemotherapeutic cytotoxicity by durvalumab was at least partially mediated via increased DNA damage; however, this effect was strongly dependent on the chemotherapy agent and cell line used. Our future studies aim to address the specific mechanisms underlying the observed ICI-induced potentiation or depotentiation.

Emerging Role of IGF-1 in Prostate Cancer: A Promising Biomarker and Therapeutic Target.

Prostate cancer (PCa) is a highly heterogeneous disease driven by gene alterations and microenvironmental influences. Not only enhanced serum IGF-1 but also the activation of IGF-1R and its downstream signaling components has been increasingly recognized to have a vital driving role in the development of PCa. A better understanding of IGF-1/IGF-1R activity and regulation has therefore emerged as an important subject of PCa research. IGF-1/IGF-1R signaling affects diverse biological processes in cancer cells, including promoting survival and renewal, inducing migration and spread, and promoting resistance to radiation and castration. Consequently, inhibitory reagents targeting IGF-1/IGF-1R have been developed to limit cancer development. Multiple agents targeting IGF-1/IGF-1R signaling have shown effects against tumor growth in tumor xenograft models, but further verification of their effectiveness in PCa patients in clinical trials is still needed. Combining androgen deprivation therapy or cytotoxic chemotherapeutics with IGF-1R antagonists based on reliable predictive biomarkers and developing and applying novel agents may provide more desirable outcomes. This review will summarize the contribution of IGF-1 signaling to the development of PCa and highlight the relevance of this signaling axis in potential strategies for cancer therapy.

A doxorubicin and siRNA coloaded nanolamellar hydroxyapatite/PLGA electrospun scaffold as a safe antitumor drug delivery system

To circumvent the severe cytotoxicity and drug resistance of chemotherapeutics in cancer chemotherapy, we rationally designed an electrospun nanofibrous delivery system for the codelivery of the doxorubicin (DOX) and small interfering ribonucleic acid (siRNA) to improve antitumor activity and mitigate DOX drug resistance. DOX was intercalated into nanolamellar hydroxyapatite (LHAp), which was incorporated into electrospun poly(lactic-co-glycolic acid) (PLGA) nanofibers, and finally, the DOX-intercalated LHAp/PLGA scaffold was coated with polydopamine (PDA) followed by immobilization with siRNA/polyethyleneimine (PEI) complexes. Benefiting from its intrinsic degradability, the scaffold demonstrated pH-responsive release behavior, leading to the simultaneous delivery of DOX and siRNA. Consequently, the codelivery scaffold demonstrated enhanced therapeutic efficiency in vitro and in vivo compared with the scaffold loaded with single drug due to the combined effects of DOX and siRNA and did not show toxicity or side effects in mice. Therefore, it is a safe and effective strategy for preventing postsurgical tumor recurrence.

Second primary malignancies in non-Hodgkin lymphoma: epidemiology and risk factors.

With the advancements in therapeutics for non-Hodgkin lymphoma (NHL), the long-term survival of patients with NHL has markedly increased. Second primary malignancies (SPMs) have become an increasingly relevant long-term concern for NHL survivors. The etiology of SPMs is multifactorial and involves multiple steps. Germline alterations, immune dysregulation, and clonal hematopoiesis contribute to the accumulation of intrinsic adverse factors, and external factors such as lifestyle; exposure to infectious factors; and late effects of radiotherapy, chemotherapy, high-dose therapy, and autologous hematopoietic stem cell transplantation further increase SPM risk. Therapy-related myeloid neoplasms (t-MNs) are a devastating complication of cytotoxic chemotherapeutic agents. However, as targeted therapies begin to replace cytotoxic chemotherapy, the incidence of t-MNs is likely to decline, particularly for indolent B-cell NHL.

Long non-coding RNAs and melanoma: From diagnosis to therapy

Although extremely rare, malignant melanoma is the deadliest type of skin malignancy with the inherent capability to invade other organs and metastasize to distant tissues. In 2021, it was estimated that approximately 106,110 patients may have received the diagnosis of melanoma, with a mortality rate of 7180. Surgery remains the common choice for treatment in patients with melanoma. Despite many advances in the treatment of melanoma, some patients, such as those who have received cytotoxic chemotherapeutic and immunotherapic agents, a significant number of patients may show inadequate treatment response following initiating these treatments. Non-coding RNAs, including lncRNAs, have become recently popular and attracted the attention of many researchers to make new insights into the pathogenesis of many diseases, particularly malignancies. LncRNAs have been thoroughly investigated in multiple cancers such as melanoma and have been shown to play a major role in regulating various physiological and pathological cellular processes. Considering their core regulatory function, these non-coding RNAs may be appropriate candidates for melanoma patients' diagnosis, prognosis, and treatment. In this review, we will cover all the current literature available for lncRNAs in melanoma and will discuss their potential benefits as diagnostic and/or prognostic markers or potent therapeutic targets in the treatment of melanoma patients.

A neutrophil-biomimic platform for eradicating metastatic breast cancer stem-like cells by redox microenvironment modulation and hypoxia-triggered differentiation therapy

Metastasis accounts for 90% of breast cancer deaths, where the lethality could be attributed to the poor drug accumulation at the metastatic loci. The tolerance to chemotherapy induced by breast cancer stem cells (BCSCs) and their particular redox microenvironment further aggravate the therapeutic dilemma. To be specific, therapy-resistant BCSCs can differentiate into heterogeneous tumor cells constantly, and simultaneously dynamic maintenance of redox homeostasis promote tumor cells to retro-differentiate into stem-like state in response to cytotoxic chemotherapy. Herein, we develop a specifically-designed biomimic platform employing neutrophil membrane as shell to inherit a neutrophil-like tumor-targeting capability, and anchored chemotherapeutic and BCSCs-differentiating reagents with nitroimidazole (NI) to yield two hypoxia-responsive prodrugs, which could be encapsulated into a polymeric nitroimidazole core. The platform can actively target the lung metastasis sites of triple negative breast cancer (TNBC), and release the escorted drugs upon being triggered by the hypoxia microenvironment. During the responsiveness, the differentiating agent could promote transferring BCSCs into non-BCSCs, and simultaneously the nitroimidazole moieties conjugated on the polymer and prodrugs could modulate the tumor microenvironment by depleting nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) and amplifying intracellular oxidative stress to prevent tumor cells retro-differentiation into BCSCs. In combination, the BCSCs differentiation and tumor microenvironment modulation synergistically could enhance the chemotherapeutic cytotoxicity, and remarkably suppress tumor growth and lung metastasis. Hopefully, this work can provide a new insight in to comprehensively treat TNBC and lung metastasis using a versatile platform.