Chemotherapeutic Therapies Research Articles

Bioinspired caffeic acid-laden milk protein-based nanoparticles targeting folate receptors for breast cancer treatment.

Breast cancer is the second leading cause of death worldwide. Conventional chemotherapeutic therapies lack the specific targeting effect toward the cancerous cells resulting in extensive side effects. Our current study endeavors to prepare novel bioinspired folic acid-functionalized caffeic acid (CA)-loaded casein nanoparticles (CS NPs) for curbing breast cancer. CA-CS NPs were prepared by simple coacervation method followed by lyophilization. Functionalized CS NPs were achieved using folic acid as the targeting moiety. Entire comparative characterization between unconjugated and conjugated NPs were implemented in terms of size, polydispersity index, surface charge, 1H-NMR, surface morphology, in-vitro drug release, sterilization, cytotoxicity, and animal studies. Conjugated NPs attained PS = 157.23 ± 2.64 nm, PDI = 0.309 ± 0.199, ZP = -25.53 ± 2.31 mV and IC50 = 40 ± 2.9 µg/ml. Significant reduction in the biochemical marker levels of Carcino-embryonic antigen, carbohydrate antigen 15-3, and malondialdehyde while increased superoxide dismutase levels were achieved in the tumor -induced rats treated by the conjugated NPs. Histopathological examinations showed great improvement in the mammary and necrotic regions. The present work paves the road of 'back to nature' approach in designing biocompatible bioinspired conjugated nanocarriers for the diagnosis and treatment of various diseases.

Identification of an inflammatory response-related gene prognostic signature and immune microenvironment for cervical cancer.

Background: Cervical cancer (CC) is the fourth most common cancer among women worldwide. As part of the brisk cross-talk between the host and the tumor, prognosis can be affected through inflammatory responses or the tumor microenvironment. However, further exploration of the inflammatory response-related genes that have prognostic value, microenvironment infiltration, and chemotherapeutic therapies in CC is needed. Methods: The clinical data and mRNA expression profiles of CC patients were downloaded from a public database for this study. In the TCGA cohort, a multigene prognostic signature was constructed by least absolute shrinkage and selection operator (LASSO) and Cox analyses. CC patients from the GEO cohort were used for validation. K‒M analysis was used to compare overall survival (OS) between the high- and low-risk groups. Univariate and multivariate Cox analyses were applied to determine the independent predictors of OS. The immune cell infiltration and immune-related functional score were calculated by single-sample gene set enrichment analysis (GSEA). Immunohistochemistry was utilized to validate the protein expression of prognostic genes in CC tissues. Results: A genetic signature model associated with the inflammatory response was built by LASSO Cox regression analysis. Patients in the high-risk group had a significantly lower OS rate. The predictive ability of the prognostic genes was evaluated by means of receiver operating characteristic (ROC) curve analysis. The risk score was confirmed to be an independent predictor of OS by univariate and multivariate Cox analyses. The immune status differed between the high-risk and low-risk groups, and the cancer-related pathways were enriched in the high-risk group according to functional analysis. The risk score was significantly related to tumor stage and immune infiltration type. The expression levels of five prognostic genes (LCK, GCH1, TNFRSF9, ITGA5, and SLC7A1) were positively related to sensitivity to antitumor drugs. Additionally, the expression of prognostic genes was significantly different between CC tissues and myoma patient cervix (non-tumorous) tissues in the separate sample cohort. Conclusion: A model consisting of 5 inflammation-related genes can be used to predict prognosis and influence immune status in CC patients. Furthermore, the inhibition or enhancement of these genes may become a novel alternative therapy.

LAG-3 : recent developments in combinational therapies in cancer.

The study of anticancer immune responses and in particular the action of immune checkpoint inhibitors that overcome T cell inhibition has revolutionized metastatic patients' care. Unfortunately, many patients are resistant to these innovative immunotherapies. Over the last decade, several immune checkpoint inhibitors, currently available in the clinic, have been developed, such as anti-PD-1/PD-L1 or anti-CTLA-4. More recently, other immune checkpoints have been characterized, among them lymphocyte activation gene 3 (LAG-3). LAG-3 has been the subject of numerous therapeutic studies and may be involved in cancer-associated immune resistance phenomena. This review summarizes the latest knowledge on LAG-3 as an immunotherapeutic target, particularly in combination with standard or innovative therapies. Indeed, many studies are looking at combining LAG-3 inhibitors with chemotherapeutic, immunotherapeutic, radiotherapeutic treatments, or adoptive cell therapies to potentiate their antitumor effects and/or to overcome patients' resistance. We will particularly focus on the association therapies that are currently in phase III clinical trials and innovative combinations in preclinical phase. These new discoveries highlight the possibility of developing other types of therapeutic combinations currently unavailable in the clinic, which could broaden the therapeutic spectrum of personalized medicine.

Abstract 3031: Overcoming drug resistance in cancer: A paradigm shift with FoxM1 targeting

Abstract In cancer treatment, overcoming drug resistance remains a formidable challenge. The oncogenic transcription factor FoxM1 is widely recognized for its crucial role in promoting drug resistance to various chemotherapeutic and target therapies. Its involvement is attributed to pivotal pathways, encompassing cell cycle progression, angiogenesis, and metastasis. Despite its prominent role in tumor drug resistance, achieving modulation of FoxM1 using small molecule therapeutics has proven elusive. 5-fluorouracil (5-FU), a commonly used chemotherapeutic agent, is known to induce a significant upregulation of FoxM1. In this study, we demonstrate that our novel compound A3 leads to a robust dose-dependent reduction of FoxM1 driven by 5-FU in HT-29 colorectal cancer cells. Notably, exposure of 5-FU-treated HT-29 cells to A3 was shown to promote apoptosis via pro-apoptotic factors, including PUMA. The mechanism of action was further elucidated through a comprehensive analysis of cell signaling molecules. This study presents an innovative approach using small molecule modulators to control FoxM1 levels, providing profound insights for potential therapeutic interventions in cancer treatment. Citation Format: Martin Pettersson, Su Jung Bae, Kyu-kwang Cho, Hye-yeoung Yun, Hee-Sung Park. Overcoming drug resistance in cancer: A paradigm shift with FoxM1 targeting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3031.

In vitro Anticancer activity of Rumex abyssinicus root extracts on breast cancer MCF-7 cell lines

Breast cancer is the leading cause of death in women. Currently existing chemopreventive and chemotherapeutic drugs promote resistance to breast treatment, and long-term usage results in unwanted side effects. Plant-derived anticancer agents have various advantages over chemical chemotherapeutic therapies, including lower cytotoxicity and higher pharmacological efficacy. Rumex abyssinicus (R. abyssinicus) has long been used as a traditional medicinal plant in Ethiopia for the treatment of infectious and non-infectious diseases. The purpose of this study is to evaluate the phytochemical analysis and investigate the in vitro cytotoxicity effect in MCF-7 breast cancer cell lines. R. abyssinicus dried roots powder was extracted with soxhlet from low polar to high polar solvents. Using established techniques, phytochemical screening of organic roots extracts of R. abyssinicus was performed. In vitro anticancer activities were evaluated by MTT assay. Among the organic root extracts of R. abyssinicus evaluated againstMCF-7 breast cancer cell lines, the chloroform extract displayed substantial in vitro cytotoxicity with an IC 50 value of 175.82g/ml. As a result, the researcher concluded that the chloroform extract of R. abyssinicus shown potential in vitro cytotoxicity in MCF-7 breast cancer cell lines.

The effect of paclitaxel- and fisetin-loaded PBM nanoparticles on apoptosis and reversal of drug resistance gene ABCG2 in ovarian cancer

BackgroundHigh-grade serous ovarian cancer (OvCa) is the most common type of epithelial OvCa. It is usually diagnosed in advanced stages, leaving a woman’s chance of survival below 50%. Despite traditional chemotherapeutic therapies, there is often a high recurrence rate following initial treatments. Hence, a targeted drug delivery system is needed to attack the cancer cells and induce apoptosis, overcome acquired drug resistance, and protect normal cells from cytotoxicity. The present study shows that targeting folate receptor alpha (FRα) through planetary ball milling (PBM) nanoparticles (NPs) induces apoptosis in OvCa cells.ResultsHuman tissue microarrays (TMAs) show overexpression of FRα in Stage IV OvCa tissues compared to matched normal tissues. They provide a focus for a targeted delivery system. We formulated PBM nanoparticles encapsulated with paclitaxel (PTX) or fisetin (Fis) and conjugated with folic acid (FA). The cytotoxic effect of these PBM NPs reduced the concentration of the toxic chemotherapy drug PTX by five-fold. The combined treatment of PTX-FA NPs and Fis-FA NPs inhibited cell proliferation and induced apoptosis more extensively than the individual drugs alone. Apoptosis of OvCa cells, determined by flow cytometry, showed an increase from 14.4 to 80.4% (OVCAR3 cells) and from 2.69 to 90.0% (CAOV3 cells) in the number of apoptotic cells. Also, expressions of the pro-apoptotic markers, BAK and active caspase-3, were increased after PTX-FA + Fis-FA PBM NP treatment. In addition to looking at targeted treatment effects on apoptosis, drug resistance was investigated. Drug resistance in OvCa cells was reversed by ABCG2, an ABC-transporter marker.ConclusionsOur study shows that PTX-FA and Fis-FA PBM NPs directly target platinum-resistant OvCa cells, induce cytotoxic/apoptotic effects, and reverse multi-drug resistance (MDR). These findings allow us to create new clinical applications using PTX-FA and Fis-FA combination nanoparticles to treat drug-resistant cancers.

Deciphering the molecular mechanistic paths describing the chemotherapeutic potential and epigenetic regulation of curcumin in lung cancer: a mini review.

In an uncontrolled inflammatory environment, the complex process of lung carcinogenesis occurs. Lung cancer remains the leading cause of cancer-related mortality worldwide. The average 5-year survival rate is still low despite significant advancements in our knowledge of lung carcinogenesis and the development of innovative therapies in recent decades. Research on adjuvant treatment, lung carcinogenesis pathways, and possible prognostic indicators has to be refocused using an innovative approach. The majority of lung cancers are discovered at an advanced stage when there is little chance of recovery. It has grown in popularity in recent years to supplement already available chemotherapeutic therapies with adjuvant herbal medications, which may lessen toxicity and adverse effects without sacrificing therapeutic efficiency. One such prospective contender is curcumin. In-depth research has been done on curcumin as a multi-target anti-tumor and anti-inflammatory molecule. A pharmacologically active polyphenol produced from turmeric is called curcumin. Over the past few decades, curcumin's therapeutic potential has been thoroughly studied, and data indicate that curcumin may play a part in a variety of biological processes, most notably its potent anticancer activity. Being a pleiotropic chemical, curcumin regulates a variety of molecules that are key players in many cell signaling pathways. It has been shown to stifle transformation, restrain proliferation, and trigger apoptosis. Curcumin can reduce the development of non-small cell LC by downregulating Circular RNA hsa_circ_0007580, which in turn controls the expression of integrin subunit beta 1 by adsorbing miR-384. Nevertheless, despite all these advantages, curcumin's effectiveness is still restricted because of its weak bioavailability, poor absorption within the systemic circulation, and quick removal from the body. In an effort to overcome these constraints, scientists from all around the world are working to develop a synthetic and improved curcuminoid by appropriately altering the parent skeleton structurally. These curcuminoids will simultaneously improve the physicochemical properties and efficacy. This review presents evidence from the most recent clinical trials coupled with the molecular mechanisms of curcumin in LC.

A comprehensive overview on antibody-drug conjugates: from the conceptualization to cancer therapy.

Antibody-Drug Conjugates (ADCs) represent an innovative class of potent anti-cancer compounds that are widely used in the treatment of hematologic malignancies and solid tumors. Unlike conventional chemotherapeutic drug-based therapies, that are mainly associated with modest specificity and therapeutic benefit, the three key components that form an ADC (a monoclonal antibody bound to a cytotoxic drug via a chemical linker moiety) achieve remarkable improvement in terms of targeted killing of cancer cells and, while sparing healthy tissues, a reduction in systemic side effects caused by off-tumor toxicity. Based on their beneficial mechanism of action, 15 ADCs have been approved to date by the market approval by the Food and Drug Administration (FDA), the European Medicines Agency (EMA) and/or other international governmental agencies for use in clinical oncology, and hundreds are undergoing evaluation in the preclinical and clinical phases. Here, our aim is to provide a comprehensive overview of the key features revolving around ADC therapeutic strategy including their structural and targeting properties, mechanism of action, the role of the tumor microenvironment and review the approved ADCs in clinical oncology, providing discussion regarding their toxicity profile, clinical manifestations and use in novel combination therapies. Finally, we briefly review ADCs in other pathological contexts and provide key information regarding ADC manufacturing and analytical characterization.

Curcumin‐loaded nanomedicines as therapeutic strategy in malaria management

AbstractMalaria, a parasitic protozoan disease widespread in tropical climates, is transmitted by Plasmodium spp. Many people are affected by this significant public health disease, which has a high incidence of illness and mortality worldwide. Because drug‐resistant parasites are on the rise, there are not enough controls on mosquitoes, and there are not any malaria vaccinations. Malaria is particularly challenging in developing countries. Antimalarial drugs approved by Food and Drug Administration are the main options for combating and preventing malaria; also the control of transmission at the level of mosquitoes is important. Current antimalarial chemotherapeutic therapies have significant clinical flaws such as Plasmodium resistance, the drugs that call for the development of novel drug candidates. To combat malaria, nanotechnology may give a viable alternative that is both more effective and safer than current treatment options. Nanotechnology‐based curcumin formulations have proved to overcome the limitations of current therapies in terms of optimum therapeutic benefits, safety, and cost‐efficiency, which increases a patient's capacity to adhere to prescribed medicine. The limits of current malaria therapies and the need to employ nanotechnological curcumin to treat malaria were addressed and discussed in this paper.

Oral chemotherapeutic agents in metastatic hormone-sensitive prostate cancer: A network meta-analysis of randomized controlled trials.

Multiple oral chemotherapeutic agents for metastatic hormone-sensitive prostate cancer (mHSPC) have been developed for conjugated use with conventional androgen deprivation therapy (ADT). Several randomized controlled trials (RCTs) report significant benefits in mHSPC patients. Therefore, we compared overall survival (OS) and progression-free survival (PFS) benefits among considerable mHSPC oral chemotherapeutic agents. We investigated mHSPC treatment efficacy through a systematic RCT-trial literature review (PubMed, Embase, Web of Science, the Cochrane Library, and Scopus). Two reviewers independently screened, extracted data, and assessed bias risk in duplicate. We identified 18 RCTs (n=13,509). Concerning OS, ADT+abiraterone, ADT+abiraterone+docetaxel, ADT+apalutamide, ADT+bicalutamide, ADT+darolutamide+docetaxel, ADT+enzalutamide, ADT+orteronel, and ADT+rezvilutamide were more effective than the standard of care (SOC). Comparing PFS, most treatments were more effective than SOC, excluding ADT+bicalutamide, nilutamide, flutamide, ADT+bicalutamide+palbociclib, and ADT+nilutamide. ADT+docetaxel with androgen receptor targeted agent (ARTA) triplet therapy was not among the top three treatments determined through ranking analysis. Novel oral chemotherapeutic agent combination therapies must replace current ADT monotherapy and ADT+docetaxel SOC. Even so, ADT+docetaxel with ARTA triplet therapy still is not the best mHSPC treatment and requires further study.

Ocular adverse effects of anti-cancer chemotherapy.

Cancer ranks as the second leading cause of mortality in Europe, following cardiovascular diseases. Every year, 2.6 million people are diagnosed with this disease, and 1.2 million die. It has an impact not only on individual health but also on society and the economy. The survival rate has improved with the introduction of new diagnostic methods and anti-cancer chemotherapy. While more aggressive chemotherapeutic regimens and combination therapies have demonstrated efficacy against cancer cells, they also have detrimental effects on normal cells, leading to systemic and ocular adverse reactions associated with cytotoxicity, inflammation, and neurotoxicity. Consequently, we have an increased survival rate, but the appearance of these ocular adverse effects decreases the quality of life. Ocular toxicity induced by chemotherapeutic agents is often underestimated. While prevention may not be possible, proper management by an ophthalmologist, an integral part of the oncology patient's medical team, is crucial. The ophthalmologist should assess the patient before initiating chemotherapeutic treatment and continue monitoring throughout to identify any adverse ocular reactions resulting from the systemic chemotherapy. This article aimed to briefly highlight the adverse reactions occurring at the ocular surface in patients undergoing chemotherapeutic treatment. Fortunately, these ocular side effects are limited only to the period in which the chemotherapeutic treatment is done, with most of them disappearing a few weeks after stopping the treatment.

Abstract 6559: Model constructed by ferroptosis-related genes and m6A genes predicts the sensitivity to different drug treatments

Abstract Background: Immune checkpoint blockade (ICB) therapies exhibit distinct response in hepatocellular carcinoma (HCC) patients, therefore biomarkers to screen beneficial patients remains an urgent need in clinical practice. Ferroptosis, an unique form of programmed cell death (PCD), has been implicated in the carcinogenesis and considered as one of the underlying mechanism of targeted and chemotherapeutic therapies in HCC. N6-methyladenosine (m6A), the most dominant form of RNA post-transcriptional modification, has been reported to regulat cancer-associated genes, including ferroptosis-related genes. Methods: Differentially expressed genes (DEGs) between tumor and normal tissues were screened from TCGA-LIHC dataset. The overlap of DEGs and ferroptosis-related genes (FRGs) resulted in a set of 51 genes. These genes together with 22 m6A-related genes were next subjected to univariate Cox regression for their association with survival. In total, 35 genes showed significant association with survival in this analysis, and they were then used to construct the regression model by Lasso-Cox regression analysis. We then validated the performance of the signature derived from the model in TCGA-LIHC and an external dataset (GSE14520). The signature was also examined for their association with immune-related characters, and their performance in predicting drug response using datasets of immunotherapy cohort studies and cellular experimental studies. Results: We constructed this prognosis model by expression level of four genes (G6PD, YTHDF1, STMN1, and SLC7A11). Patients with a high-risk score of the signature have a shortened survival time, and the signature is an independent predictor of the prognosis. We also found that the difference between the risk score before and after ICB treatment was significantly associated with sensitivity to the treatment: an increase in the risk score after the treatment correlated with an adverse response. Using the in vitro cellular experimental dataset, we detected a positive association between the risk score and the sensitivity to 5-fluorouracil and sorafenib. Conclusion: The prognosis signature constructed by four ferroptosis- and m6A- related genes exhibited promising predictive value for OS of HCC patients. The signature could also indicate the sensitivity for different kinds of clinical treatment. A higher risk score indicated a higher resistance for immunotherapy but a higher sensitivity for chemotherapy and RTKs inhibitor. The results of this study not only help to improve the clinical practice of HCC, but also provide new insights into unveiling the underlying mechanisms of tumorigenesis and progression. Citation Format: Tao Han, Mengyuan Liu. Model constructed by ferroptosis-related genes and m6A genes predicts the sensitivity to different drug treatments [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 6559.

Cuproptosis-related gene index: A predictor for pancreatic cancer prognosis, immunotherapy efficacy, and chemosensitivity.

AimThe term “Cuproptosis” was coined to describe a novel type of cell death triggered by intracellular copper buildup that is fundamentally distinct from other recognized types such as autophagy, ferroptosis, and pyroptosis in recent days. As the underlying mechanism was newly identified, its potential connection to pancreatic adenocarcinoma (PAAD) is still an open issue.MethodsA set of machine learning algorithms was used to develop a Cuproptosis-related gene index (CRGI). Its immunological characteristics were studied by exploring its implications on the expression of the immunological checkpoints, prospective immunotherapy responses, etc. Moreover, the sensitivity to chemotherapeutic drugs was predicted. Unsupervised consensus clustering was performed to more precisely identify different CRGI-based molecular subtypes and investigate the immunotherapy and chemotherapy efficacy. The expression of DLAT, LIPT1 and LIAS were also investigated, through real-time quantitative polymerase chain reaction (RT-qPCR), western blot, and immunofluorescence staining (IFS).ResultsA novel CRGI was identified and validated. Additionally, correlation analysis revealed major changes in tumor immunology across the high- and low-CRGI groups. Through an in-depth study of each medication, it was determined that the predictive chemotherapeutic efficacy of 32 regularly used anticancer drugs differed between high- and low-CRGI groups. The results of the molecular subtyping provided more support for such theories. Expressional assays performed at transcriptomic and proteomic levels suggested that the aforementioned Cuproptosis-related genes might serve as reliable diagnostic biomarkers in PAAD.SignificanceThis is, to the best of our knowledge, the first study to examine prognostic prediction in PAAD from the standpoint of Cuproptosis. These findings may benefit future immunotherapy and chemotherapeutic therapies.

Novel Approaches Used in Ovarian Tissue Transplantation for Fertility Preservation: Focus on Tissue Engineering Approaches and Angiogenesis Capacity.

Due to the impact of the modern lifestyle, female infertility has been reduced because of different reasons. For example, in combined chemotherapeutic therapies, a small fraction of cancer survivors has faced different post-complications and side effects such as infertility. Besides, in modern society, delayed age of childbearing has also affected fertility. Nowadays, ovarian tissue cryopreservation and transplantation (OTC/T) is considered one of the appropriate strategies for the restoration of ovarian tissue and bioactivity in patients with the loss of reproductive function. In this regard, several procedures have been considered to improve the efficacy and safety of OTT. Among them, a surgical approach is used to transplant ovaries into the optimal sites, but the existence of ischemic changes and lack of appropriate revascularization can lead to bulk follicular atresia. Besides, the role of OTC/T is limited in women of advanced maternal age undergoing lifesaving chemo-radiation. As a correlate, the development of de novo approaches with efficacious regenerative outcomes is highly welcomed. Tissue engineering shows high therapeutic potentialities to restore fertility in males and females using the combination of biomaterials, cells, and growth factors. Unfortunately, most synthetic and natural materials are at the experimental stage and only the efficacy has been properly evaluated in limited cases. Along with these descriptions, strategies associated with the induction of angiogenesis in transplanted ovaries can diminish the injuries associated with ischemic changes. In this review, the authors tried to summarize recent techniques, especially tissue engineering approaches for improving ovarian function and fertility by focusing on angiogenesis and neovascularization.

Abstract 1286: Oral administration of poly gamma glutamic acid significantly enhances the antitumor immune response of doxorubicin in a murine cancer model through regulating tumor microenvironment

Abstract Immunogenic cell death (ICD) is a type of cancer cell death triggered by certain chemotherapeutic drugs, oncolytic viruses, and other therapies. In particular, doxorubicin (DOX), one of the chemo-drugs, is well known to induce ICD, which involves the activation of the immune system against cancer in immunocompetent hosts. ICD comprises the release of damage-associated molecular patterns (DAMPs) from dying tumor cells that result in the activation of tumor-specific immune responses, thus eliciting long-term efficacy of anticancer drugs by combining direct cancer cell killing and antitumor immunity. However, the antitumor immunity can be achieved by overcoming the immunosuppressive tumor microenvironment (TME). Most current treatment strategies harnessing the tumor microenvironment focus on T cell-immune response, either by promoting activating signals or suppressing inhibitory ones.We here present a novel approach to cope with the inhibitory TME, combinatory treatment of DOX with poly gamma glutamic acid (γ-PGA). PGA, a safe edible biomaterial secreted by B. subtillis, has been evaluated in the clinical trials with the patients diagnosed as cervical intraepithelial neoplasia 1 (CIN 1). From the study using murine cancer models, including MC38, we found the combinatory treatment with γ-PGA restored the downregulation of NK cell activity caused by DOX, enhanced ICD and T cell responses, and reduced proinflammatory cytokines in the tumor tissues. Taken together, co-administration of γ-PGA exhibited synergistic anti-cancer effects by favoring the immunosuppressive TME in the combinatory treatment with conventional chemo-drugs. Citation Format: Joungwoo Choi, Solmin Jung, Yena Oh, Jaepyeong Jang, Yeondong Cho, Do young Lee, Youngcheol Park, Kwangil Jeong. Oral administration of poly gamma glutamic acid significantly enhances the antitumor immune response of doxorubicin in a murine cancer model through regulating tumor microenvironment [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 1286.

The interactive effect of amlodipine and chemotherapeutic agents in lung cancer cells

Chemoresistance is one of the major challenges in lung cancer treatment. The identification of new chemotherapeutic therapies with increased efficacy and minimal toxicity over those currently in use is a key area of current research. Calcium channel blockers are emerging as anticancer agents in lung and other cancers. This study evaluates the ability of amlodipine to sensitize non-small cell lung cancer (NSCLC) cells to the first-line chemotherapeutics used in lung cancer treatment. Cell viability in the presence of carboplatin, gemcitabine, pemetrexed, or paclitaxel alone or combined with amlodipine was evaluated in A549 and H1299 NSCLC cell lines using the colorimetric MTT cell proliferation assay. Nonlinear regression curve fit analyses were used to calculate half-maximal inhibitory concentrations (IC50). Sensitization was estimated by the ratio of the IC50 of the monotherapy to the IC50 of the combined therapy that included that drug (R-value). We found that amlodipine significantly reduced cell viability in a dose-dependent manner, with IC50 values of 23 and 25.66 μM in A549 and H1299 NSCLC cells, respectively. In addition, amlodipine combined with carboplatin, gemcitabine, pemetrexed, or paclitaxel had a significant sensitization effect on A549 and H1299 NSCLC cells compared to their single-drug treatments (R > 1.0). Our findings confirm the ability of amlodipine to sensitize NSCLC cells to first-line chemotherapy treatments.

Targeted carbon monoxide delivery combined with chemodynamic, chemotherapeutic and photothermal therapies for enhanced antitumor efficacy

Polydopamine-coated hollow mesoporous copper sulfide loaded with DHA and CO-releasing molecules selectively delivered DHA and CO to tumor cells under 808 nm light irradiation, demonstrating multimodal synergistic antitumor efficacy.

Activation of Cascade-Like Antitumor Immune Responses through In Situ Doxorubicin Stimulation and Blockade of Checkpoint Coinhibitory Receptor TIGIT.

Although T cell centered immune checkpoint blockade (ICB) therapies have shown unprecedented success in various cancer types, only a minority of patients benefit from these treatments due to the lack of neoantigen burden and exhaustion of tumor-infiltrating immune stimulating cells. Inspired by the crucial role of NK cell based immunity and potential immunostimulating effect of chemotherapeutic drugs, the therapeutic efficiency on tumor inhibition through combination of doxorubicin (DOX) and blockade of TIGIT (T-cell Ig and ITIM domain), a coinhibitory receptor expressed by both NK and T cells, in a matrix metalloproteinase 2 (MMP-2)-degradable hydrogel is thoroughly evaluated in this study. Due to the distinct release kinetics from destructed framework of hydrogels, the differentially released DOX and anti-TIGIT monoclonal antibody (aTIGIT) molecules can elicit immunogenic tumor microenvironment and reverse the exhaustion of NK and effector T cells to realize not only durable localized tumor inhibition but also systemic and long-lasting immune memory responses. Thus, this work pioneers the union of chemotherapeutic drugs and NK cell centered ICB therapies for activating cascade-like antitumor immune responses through eliciting immunogenic tumor microenvironment and boosting both innate and adaptive immunity.

Glioma Stem-Like Cells and Metabolism: Potential for Novel Therapeutic Strategies

Glioma stem-like cells (GSCs) were first described as a population which may in part be resistant to traditional chemotherapeutic therapies and responsible for tumour regrowth. Knowledge of the underlying metabolic complexity governing GSC growth and function may point to potential differences between GSCs and the tumour bulk which could be harnessed clinically. There is an increasing interest in the direct/indirect targeting or reprogramming of GSC metabolism as a potential novel therapeutic approach in the adjuvant or recurrent setting to help overcome resistance which may be mediated by GSCs. In this review we will discuss stem-like models, interaction between metabolism and GSCs, and potential current and future strategies for overcoming GSC resistance.

HBV Reactivation During the Treatment of Non-Hodgkin Lymphoma and Management Strategies.

Hepatitis B virus reactivation (HBV-R), which can lead to HBV-related morbidity and mortality, is a common and well-known complication that occurs during the treatment of non-Hodgkin lymphoma (NHL) patients with current or past exposure to HBV infection. HBV-R is thought to be closely associated with chemotherapeutic or immunosuppressive therapies. However, immunosuppressive agents such as anti-CD20 antibodies (e.g., rituximab and ofatumumab), glucocorticoids, and hematopoietic stem cell transplantation (HSCT) administered to NHL patients during treatment can cause deep immunodepression and place them at high risk of HBV-R. In this review, we explore the current evidence, the guidelines of several national and international organizations, and the recommendations of expert panels relating to the definition, risk factors, screening and monitoring strategies, whether to use prophylaxis or pre-emptive therapy, and the optimal antiviral agent and duration of antiviral therapy for HBV-R.