Cytotoxic Chemotherapeutic Agents Research Articles

Advancing Immunotherapy in Pancreatic Cancer

Pancreatic cancer remains one of the deadliest malignancies, with a consistently low five-year survival rate for the past several decades. This is in stark contrast to other cancers, which have seen significant improvement in survival and prognosis due to recent developments in therapeutic modalities. These modest improvements in pancreatic cancer outcomes have primarily resulted from minor advances in cytotoxic chemotherapeutics, with limited progress in other treatment approaches. A major focus of current therapeutic research is the further development of immunomodulatory therapies characterized by antibody-based approaches, cellular therapies, and vaccines. Although initial results utilizing immunotherapy in pancreatic cancer have been mixed, recent clinical trials have demonstrated significant improvements in patient outcomes. In this review, we detail these three approaches to immunomodulation, highlighting their common targets and distinct shortcomings, and we provide a narrative summary of completed and ongoing clinical trials that utilize these approaches to immunomodulation. Within this context, we aim to inform future research efforts by identifying promising areas that warrant further exploration.

Exploring the Mechanism of Cytotoxic Activity of β-Caryophyllene Oxide and its Potential to Enhance the Activity of Doxorubicin

Plant-derived compounds, including flavonoids, sesquiterpenes, and others, have been widely investigated for their role in cancer treatment. Here, we highlight the significance of some natural compounds (β-caryophyllene oxide) in enhancing doxorubicin's chemotherapeutic cytotoxicity. We also determined a novel mechanism of cytotoxicity for β-caryophyllene oxide by revealing its ability to bind with the DNA. This potentially causes its cytotoxicity when added alone and its ability to enhance doxorubicin's cytotoxicity. We also show that some natural compounds (epicatechin) may provide protection to cancer cells against doxorubicin's toxicity. This is most likely caused by their antioxidant behavior which potentially suppressed the doxorubicin-induced reactive oxygen species (ROS) resulting in a decrease in its cytotoxicity. Moreover, similar suppression in the cytotoxicity of β-caryophyllene oxide was noticed when incubated with the other flavonoids.

Cytotoxicity of bendamustine, alone and in combination with novel agents, toward adult T-cell leukemia cells.

Adult T-cell leukemia/lymphoma (ATL) develops from the infection of T cells with human T lymphotropic virus type 1 (HTLV-1). There are an estimated 5-20 million HTLV-1 carriers worldwide and the patients are frequently observed in subtropical Africa, the Caribbean, Middle East, South America, and South West Japan. The prognosis of ATL remains dismal due to rapid acquired resistance to treatment with cytotoxic chemotherapeutic agents. In particular, the development of novel therapies for relapsed or refractory (R/R) ATL is an unmet need. Previous clinical trials revealed that bendamustine (BDM) was effective as the first-line treatment for indolent lymphoma and R/R cases of diffuse large B-cell lymphoma. Its major advantage is that it has few side effects such as hair loss and peripheral neuropathy, and does not impair the quality of life. However, its efficacy has not been verified for ATL in pre-clinical or clinical studies. In this study, we have shown the cytotoxicity of BDM alone and in combination with novel agents including the histone deacetylase (HDAC) inhibitor tucidinostat, the enhancer of zeste homolog 1/2 (EZH1/2) dual inhibitor valemetostat, and the Bcl2 family inhibitor ABT-737. The combined in vitro effects of BDM and tucidinostat were reproduced in a murine model without any obvious hematological toxicity. Our present results suggest that the combination of tucidinostat and BDM could additively prolong the survival of patients with R/R progressive ATL. The efficacy and safety of this combination are thus worthy of investigation in clinical settings.

Melatonin mitigates chemotherapy-induced small intestinal atrophy in rats and reduces cytotoxicity in murine intestinal organoids.

Cancer continues to pose a significant global health challenge, with gastrointestinal (GI) cancers among the most prevalent and deadly forms. These cancers often lead to high mortality rates and demand the use of potent cytotoxic chemotherapeutics. For example, 5-fluorouracil (5-FU) forms the backbone of chemotherapy regimens for various GI cancers, including colorectal cancer. While these chemotherapeutics efficiently kill cancer cells, they frequently cause off-target effects such as chemotherapy-induced mucositis (CIM), characterized by debilitating symptoms like pain, nausea, and diarrhoea, necessitating medical intervention. In this study, we elucidated the potential of melatonin and misoprostol to reduce 5-FU-induced small intestinal mucositis. Morphological and cellular changes in the jejunum, along with colonic faecal water content were quantified in rats as markers for CIM. Additionally, the effects of melatonin were investigated in vitro on 5-FU treated murine intestinal organoids. The results showed that melatonin prevented villus atrophy in the rat jejunal mucosa and upheld cell viability in murine intestinal organoids. In contrast, misoprostol alone or in combination with melatonin did not significantly affect CIM caused by 5-FU. These in vivo and in vitro experiments provided promising insights that melatonin may be used as a preventive and/or adjuvant combination therapy to prevent and reduce CIM, holding the potential to enhance cancer treatment outcomes and improve patient quality-of-life.

Exploring the potential of tocopherols: mechanisms of action and perspectives in the prevention and treatment of breast cancer.

Currently, breast cancer is the most common cause of mortalitycaused by neoplasia in women worldwide. The unmet challenges of conventional cancer therapy are chemoresistance and lack of selectivity, which can lead to serious side effects in patients; therefore,new treatments based on natural compounds that serve as adjuvants in breast cancer therapyare urgently needed. Tocopherols are naturally occurring antioxidant compounds that have shown antitumor activity against several types of cancer, including breast cancer. This review summarizes the antitumoral activity of tocopherols, such as theantiproliferative, apoptotic, anti-invasive, and antioxidant effects of tocopherols, through different molecular mechanisms. According to the studies described, α-T, δ-T and γ-T are the most studied in breast tumor cells; however, α-T and γ-T show a more critical antitumor activity and significant potential as a complements to chemotherapeutic drugs against breast cancer, enhancing toxicity against tumor cells and preventing cytotoxicity in nontumor cells. However, the possible relationship between tocopherol intake, related to concentration,and the promotion of cancer in particular cases should not be ruled out, so additional studies are required to determine the correct dose to obtain the desired antitumor effect. Moreover, nanomicelles of D-α-tocopherol have promising potential as pharmaceutical excipients for drug delivery to improve the cytotoxicity and selectivity of first-line chemotherapeutics against breast cancer.

Oral Neuropathy Associated with Commonly used Chemotherapeutic Agents: A Narrative Review.

Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent complication of cytotoxic chemotherapeutic agents; its incidence largely varies, depending on type, dose, agent and preexisting risk factors. Oral-and-perioral-CIPN (OCIPN) is underreported. Neurotoxic agents can cause jaw pain or numbness. This review aims to present available data on OCIPN RECENT FINDINGS: A narrative literature review, following SANRA guidelines was conducted. PubMed and Cochrane databases were searched until September 2023. Articles referring to neuropathy or neuropathic pain due to head and neck cancer, head and neck radiotherapy, oropharyngeal mucositis, infection or post-surgical pain were excluded. Platinum-based chemotherapeutics, taxanes, vinca alkaloids, immunomodulatory and alkylating agents can cause OCIPN. Platinum-based chemotherapeutics can cause orofacial cold sensitivity, orofacial and jaw pain, oral cavity tingling and teeth hypersensitivity. Taxanes may induce oral cavity and tongue numbness and tingling as well as hot hypersensitivity. Vinca alkaloids may cause jaw, teeth and lips pain and oral mucosa hyperalgesia. Immunomodulatory drugs can cause lips, tongue and perioral numbness, while alkylating agents induce tongue and lips tingling and teeth cold-hypersensitivity. Chemotherapy may cause OCIPN due to changes in cellular structure and function, like alterations in membrane receptors and neurotransmission. OCIPN should be documented and physicians, dentists and health care providers should be alerted.

Association of leukopenia in the development of cancer chemotherapy‐induced oral mucositis and its severity

AbstractAimTo prevent oral mucositis, it is important to understand its associated risk factors, such as highly cytotoxic chemotherapeutic agents, sex, and low body weight. However, to the best of our knowledge, no study has investigated the association between chemotherapy‐induced myelosuppression and oral mucositis in Japan. In this study, we examined the relationship between chemotherapy‐induced leukopenia and the severity of oral mucositis.MethodsWe conducted a retrospective cohort study of patients who received oral care interventions during cancer chemotherapy. Hematological values were obtained at the initiation of chemotherapy and on the proximal day of changes in the grade (Gr) of oral mucositis. The Gr of oral mucositis was assessed by dentists and dental hygienists using the Common Terminology Criteria for Adverse Events (version 5.0).ResultsThe data of 79 patients were analyzed during the study period. The incidence of oral mucositis was 7/79 (8.9%). The incidences of grades 1–4 were 4/79 (5.1%), 2/79 (2.5%), 0/79 (0%), and 1/79 (1.3%), respectively. Notably, the incidence of oral mucositis was significantly higher in patients with lower white blood cell and neutrophil counts (p < 0.01). Logistic regression analysis further revealed that patients with Gr 2 or higher leukopenia had a significantly higher risk of developing Grade 2 or higher oral mucositis (adjusted odds ratio: 5.2; 95% confidence interval: 1.60–17.0; p = 0.0062).ConclusionCancer chemotherapy induced‐oral mucositis may be at great risk in patients with Gr 2 or higher leukopenia.

Coumarin-based Aldo-Keto Reductase Family 1C (AKR1C) 2 and 3 Inhibitors.

A series of 7-substituted coumarin derivatives have been characterized as pan-aldo-keto reductase family 1C (AKR1C) inhibitors. The AKR1C family of enzymes are overexpressed in numerous cancers where they are involved in drug resistance development. 7-hydroxy coumarin ethyl esters and their corresponding amides have high potency for AKR1C3 and AKR1C2 inhibition. Coumarin amide 3a possessed IC50 values of 50 nM and 90 nM for AKR1C3 and AKR1C2, respectively, and exhibits 'drug-like' metabolic stability and half-life in human and mouse liver microsomes and plasma. Compound 3a was employed as a chemical tool to determine pan-AKR1C2/3 inhibition effects both as a radiation sensitizer and as a potentiator of chemotherapy cytotoxicity. In contrast to previously reported pan-AKR1C inhibitors, 3a demonstrated no radiation sensitization effect in a radiation-resistant prostate cancer cell line model. Pan-AKR1C inhibition also did not potentiate the in vitro cytotoxicity of ABT-737, daunorubicin or dexamethasone, in two patient-derived T-cell ALL and pre-B-cell ALL cell lines. In contrast, a highly selective AKR1C3 inhibitor, compound K90, enhanced the cytotoxicity of both ABT-737 and daunorubicin in the T-cell ALL cell line model. Thus, the inhibitory profile of the AKR1C family inhibitor required to effect enhancement of chemotherapeutic cytotoxicity may be chemotherapeutic agent-specific in leukemia.

Investigating druggable kinases for targeted therapy in retinoblastoma.

Retinoblastoma (RB) is a childhood retinal neoplasm and commonly treated with cytotoxic chemotherapeutic agents. However, these therapeutic approaches often lead to diverse adverse effects. A precise molecular therapy will alleviate these side effects and offer better treatment outcomes. Over the years, kinases have become potential drug targets in cancer therapy. Hence, we aimed to investigate genetic alterations of putative kinase drug targets in RB. Targeted exome sequencing was performed on 35 RB tumors with paired blood samples using a gene panel consisting of 29 FDA-approved kinase genes. Single nucleotide variants were analyzed for pathogenicity using an in-house pipeline and copy number variations (CNVs) were detected by a depth of coverage and CNVPanelizer. The correlation between genetic changes and clinicopathological features was assessed using GraphPad Prism. Three somatic mutations, two in ERBB4 and one in EGFR were identified. Two of these mutations (ERBB4 c.C3836A & EGFR c.A1196T) were not reported earlier. CNV analysis revealed recurrent gains of ALK, MAP2K2, SRC, STK11, and FGFR3 as well as frequent losses of ATM, PI3KCA and ERBB4. Notably, nonresponsive tumors had a higher incidence of amplifications in clinically actionable genes such as ALK. Moreover, ALK gain and ATM loss were strongly correlated with optic nerve head invasion. In conclusion, our study revealed genetic alterations of druggable kinases in RB, providing preliminary insights for the exploration of kinase-targeted therapy in RB.

Lumbrokinase Extracted from Earthworms Synergizes with Bevacizumab and Chemotherapeutics in Treating Non-Small Cell Lung Cancer by Targeted Inactivation of BPTF/VEGF and NF-κB/COX-2 Signaling.

As a kind of proteolytic enzyme extracted from earthworms, lumbrokinase has been used as an antithrombotic drug clinically. Nevertheless, its potential in anti-cancer, especially in anti-non-small cell lung cancer (NSCLC), as a single form of treatment or in combination with other therapies, is still poorly understood. In this study, we explored the anti-tumor role and the responsive molecular mechanisms of lumbrokinase in suppressing tumor angiogenesis and chemoresistance development in NSCLC and its clinical potential in combination with bevacizumab and chemotherapeutics. Lumbrokinase was found to inhibit cell proliferation in a concentration-dependent manner and caused metastasis suppression and apoptosis induction to varying degrees in NSCLC cells. Lumbrokinase enhanced the anti-angiogenesis efficiency of bevacizumab by down-regulating BPTF expression, decreasing its anchoring at the VEGF promoter region and subsequent VEGF expression and secretion. Furthermore, lumbrokinase treatment reduced IC50 values of chemotherapeutics and improved their cytotoxicity in parental and chemo-resistant NSCLC cells via inactivating the NF-κB pathway, inhibiting the expression of COX-2 and subsequent secretion of PGE2. LPS-induced NF-κB activation reversed its inhibition on NSCLC cell proliferation and its synergy with chemotherapeutic cytotoxicity, while COX-2 inhibitor celecoxib treatment boosted such effects. Lumbrokinase combined with bevacizumab, paclitaxel, or vincristine inhibited the xenograft growth of NSCLC cells in mice more significantly than a single treatment. In conclusion, lumbrokinase inhibited NSCLC survival and sensitized NSCLC cells to bevacizumab or chemotherapeutics treatment by targeted down-regulation of BPTF/VEGF signaling and inactivation of NF-κB/COX-2 signaling, respectively. The combinational applications of lumbrokinase with bevacizumab or chemotherapeutics are expected to be developed as promising candidate therapeutic strategies to improve the efficacy of the original monotherapy in anti-NSCLC.

Treatment rationale and protocol design: an investigator-initiated phase II study of combination treatment of nivolumab and TM5614, a PAI-1 inhibitor for previously treated patients with non-small cell lung cancer.

There is no established standard 3rd line treatment for patients with advanced non-small cell lung cancer (NSCLC). Although cytotoxic chemotherapeutic agents that are not used as 1st or 2nd line treatment are administrated as 3rd line treatment, their anti-tumor efficacy is insufficient. Anti-programmed death ligand-1 (PD-L1)/programmed death-1 (PD1) treatment is more effective and less toxic than chemotherapy in anti-PD-L1/PD-1 treatment-naïve patients with NSCLC. Therefore, anti-PD-L1/PD-1 therapy is considered an appropriate 3rd line treatment. However, the anti-tumor efficacy is limited in patients previously treated with anti-PD-L1/PD-1 antibody. Today, new drugs are needed to increase the efficacy of anti-PD-L1/PD-1 antibodies. This open-label, single-arm, investigator-initiated phase II study is designed to evaluate combination treatment of nivolumab and TM5614, a plasminogen activator inhibitor (PAI-1) inhibitor as 3rd or more line treatment in NSCLC patients who underwent standard treatment. The primary endpoint is the objective response rate and the secondary endpoints are progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. Recruitment began in September 2023 and is expected to continue for approximately three years. Currently, there is no standard 3rd line treatment for advanced NSCLC, and we hope that the findings of this study will facilitate more effective treatments in this setting. Ethics and dissemination: the study protocol conformed to the ethical principles outlined in the Declaration of Helsinki. All patients will provide written informed consent prior to enrollment. Results will be published in a peer-reviewed publication. This study is registered to Japan Registry of Clinical Trials with number: jRCT2061230039 (19/July/2023).

Dose Optimization in Oncology Drug Development: An International Consortium for Innovation and Quality in Pharmaceutical Development White Paper.

The landscape of oncology drug development has witnessed remarkable advancements over the last few decades, significantly improving clinical outcomes and quality of life for patients with cancer. Project Optimus, introduced by the U.S. Food and Drug Administration, stands as a groundbreaking endeavor to reform dose selection of oncology drugs, presenting both opportunities and challenges for the field. To address complex dose optimization challenges, an Oncology Dose Optimization IQ Working Group was created to characterize current practices, provide recommendations for improvement, develop a clinical toolkit, and engage Health Authorities. Historically, dose selection for cytotoxic chemotherapeutics has focused on the maximum tolerated dose, a paradigm that is less relevant for targeted therapies and new treatment modalities. A survey conducted by this group gathered insights from member companies regarding industry practices in oncology dose optimization. Given oncology drug development is a complex effort with multidimensional optimization and high failure rates due to lack of clinically relevant efficacy, this Working Group advocates for a case-by-case approach to inform the timing, specific quantitative targets, and strategies for dose optimization, depending on factors such as disease characteristics, patient population, mechanism of action, including associated resistance mechanisms, and therapeutic index. This white paper highlights the evolving nature of oncology dose optimization, the impact of Project Optimus, and the need for a tailored and evidence-based approach to optimize oncology drug dosing regimens effectively.

DNA-protein crosslinks are key to platinum-based chemotherapeutic cytotoxicity

DNA-protein crosslinks are key to platinum-based chemotherapeutic cytotoxicity

Innovative Nanoparticulate Strategies in Colon Cancer Treatment: A Paradigm Shift.

As a major public health issue, colorectal cancer causes 9.4% of total cancer-related deaths and comprises 10% of new cancer diagnoses worldwide. In the year 2023, an estimated 153,020 people are expected to receive an identification of colorectal cancer (CRC), resulting in roughly 52,550 fatalities anticipated as a result of this illness. Among those impacted, approximately 19,550 cases and 3750 deaths are projected to occur in individuals under the age of 50. Irinotecan (IRN) is a compound derived from the chemical structure of camptothecin, a compound known for its action in inhibiting DNA topoisomerase I. It is employed in the treatment strategy for CRC therapies. Comprehensive in vivo and in vitro studies have robustly substantiated the anticancer efficacy of these compounds against colon cancer cell lines. Blending irinotecan in conjunction with other therapeutic cancer agents such as oxaliplatin, imiquimod, and 5 fluorouracil enhanced cytotoxicity and improved chemotherapeutic efficacy. Nevertheless, it is linked to certain serious complications and side effects. Utilizing nano-formulated prodrugs within "all-in-one" carrier-free self-assemblies presents an effective method to modify the pharmacokinetics and safety portfolio of cytotoxic chemotherapeutics. This review focuses on elucidating the mechanism of action, exploring synergistic effects, and innovating novel delivery approaches to enhance the therapeutic efficacy of irinotecan.

Design, synthesis, and evaluation of cyclic C7-bridged monocarbonyl curcumin analogs containing an o-methoxy phenyl group as potential agents against gastric cancer

The structure-activity relationship (SAR) between toxicity and the types of linking ketones of C7 bridged monocarbonyl curcumin analogs (MCAs) was not clear yet. In the pursuit of effective and less cytotoxic chemotherapeutics, we conducted a SAR analysis using various diketene skeletons of C7-bridged MCAs, synthesized cyclic C7-bridged MCAs containing the identified low-toxicity cyclopentanone scaffold and an o-methoxy phenyl group, and assessed their anti-gastric cancer activity and safety profile. Most compounds exhibited potent cytotoxic activities against gastric cancer cells. We developed a quantitative structure-activity relationship model (R 2 > 0.82) by random Forest method, providing important information for optimizing structure. An optimized compound 2 exhibited in vitro and in vivo anti-gastric cancer activity partly through inhibiting the AKT and STAT3 pathways, and displayed a favorable in vivo safety profile. In summary, this paper provided a promising class of MCAs and a potential compound for the development of chemotherapeutic drugs.

Abstract A049: Epithelial to mesenchymal transition confers sensitivity to cytotoxic agent Ophiobolin A via alterations in mitochondrial function and metabolic pathways

Abstract Triple negative breast cancer (TNBC) is characterized by its high metastatic potential, resistance to therapeutics and elevated degree of disease reoccurrence. In patients with TNBC, metastasis occurs in approximately half of all cases and is tightly correlated with poor overall survival, made worse by limited therapeutic options. Metastatic events are hypothesized to be facilitated by the epithelial to mesenchymal transition (EMT), gaining enhanced self-renewal, migration, invasion and multidrug resistant capabilities. Thus, targeting these cells remains a primary therapeutic goal, despite significant difficulty. Previous attempts in pursuing these cells through cytotoxic chemotherapeutics or targeted agents has largely failed to significantly improve patient outcomes. However, the fungus-derived sesterterpenoid Ophiobolin A (OpA) has demonstrated nanomolar cytotoxic capabilities and a high therapeutic index, specific to EMT+cells in breast cancer. The properties conferring this sensitivity, and possible novel therapeutic target, though, remain unclear. As the drug-like small molecule presents a major therapeutic opportunity, the details of its mechanism of action must be determined. To this end, we generated mitochondrial cybrids and quantified activity in individual electron transport chain (ETC) complexes, and found OpA to act in a mitochondria-targeted manner. Expanding upon this, we designed an EMT based model of breast cancer and examined alterations in mitochondrial function and metabolic pathways. Targeted liquid chromatography-mass spectronomy of metabolites indicated significant variations in many of those involved in glycolysis, OXPHOS and glutaminolysis. Flow cytometry further revealed a significant decrease in membrane potential and increase in mitochondrial reactive oxygen species (ROS), indicating mitochondrial damage. Dynamic changes between OXPHOS and glycolysis were also detected via Seahorse Bioanalyzer. Transmission electron microscopy (TEM) images and fluorescent microscopy showed distinct alterations in mitochondrial morphology, spatial dynamics and network integrity. Finally, using targeted fluorescent staining, an increase in mitochondrial labile iron was uncovered. This work reveals novel metabolic variations in the context of EMT and exploitable therapeutic targets. Thus, based on these EMT-specific responses, we conclude that EMT imparts distinct alterations to mitochondrial function and metabolic pathways, conferring sensitivity to the cytotoxic effects of OpA. Citation Format: Haleigh Parker, Kayla Haberman, Alexander Kornienko, Antonio Evidente, Daniel Romo, Benny Kaipparettu, Joseph Taube. Epithelial to mesenchymal transition confers sensitivity to cytotoxic agent Ophiobolin A via alterations in mitochondrial function and metabolic pathways [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A049.

Advances in the study of marketed antibody-drug Conjugates (ADCs) for the treatment of breast cancer.

Breast cancer continues to have a high incidence rate among female malignancies. Despite significant advancements in treatment modalities, the heterogeneous nature of breast cancer and its resistance to various therapeutic approaches pose considerable challenges. Antibody-drug conjugates (ADCs) effectively merge the specificity of antibodies with the cytotoxicity of chemotherapeutic agents, offering a novel strategy for precision treatment of breast cancer. Notably, trastuzumab emtansine (T-DM1) has provided a new therapeutic option for HER2-positive breast cancer patients globally, especially those resistant to conventional treatments. The development of trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) has further broadened the applicability of ADCs in breast cancer therapy, presenting new hopes for patients with low HER2 expression and triple-negative breast cancer. However, the application of ADCs presents certain challenges. For instance, their treatment may lead to adverse reactions such as interstitial lung disease, thrombocytopenia, and diarrhea. Moreover, prolonged treatment could result in ADCs resistance, complicating the therapeutic process. Economically, the high costs of ADCs might hinder their accessibility in low-income regions. This article reviews the structure, mechanism of action, and clinical trials of commercially available ADCs for breast cancer treatment, with a focus on the clinical trials of the three drugs, aiming to provide insights for clinical applications and future research.

Elafibranor emerged as a potential chemotherapeutic drug for non-muscle invasive bladder cancer

Intravesical infusion of chemotherapeutics is highly recommended by several clinical guidelines for treating nonmuscle invasive bladder cancer (NMIBC). However, cytotoxic chemotherapeutics can cause a series of side effects, which greatly limits their application. Herein, a starvation therapy strategy was proposed, and elafibranor (ELA) was validated as a safe chemotherapeutic for NMIBC. The results showed that 20 μM ELA was sufficient to inhibit the proliferation and migration of bladder cancer cells and increase the level of intracellular reactive oxygen species (ROS). Furthermore, 2 mg/kg ELA treatment blocked the growth of primary tumors in an immunodeficient model by inhibiting proliferation and inducing apoptosis and improved the survival time of immunocompetent model mice. ELA treatment up to 10 mg/kg met the general safety requirements. We also established a patient-derived conditional reprogramming cell (CRC) model to assess the clinical translational potential of ELA. The antitumor effect and antitumor specificity of ELA treatment were confirmed. This work not only identified a promising chemotherapeutic for NMIBC but also provided a potential methodological system for drug discovery.

Microfluidic nanoparticle synthesis for oral solid dosage forms: A step toward clinical transition processes

Nanomedicine provides various opportunities for addressing medical challenges associated with drug bioavailability, stability, and efficacy. In particular, oral nanoparticles (NPs) represent an alternative strategy to enhance the solubility and stability of active ingredients through the gastrointestinal tract. The nanocarriers could be used for both local and systemic targeting, enabling controlled release of encapsulated drugs. This approach allows more efficient therapies.In this work, we aim to develop reliable oral solid dosage forms incorporating NPs produced by either one pot synthesis or continuous production, following protocols that yield highly consistent outcomes, promoting their technology transfer and clinical use.Microfluidics technology was selected to allow an automated and highly productive synthetic approach suitable for the highly throughput production.In particular, innovative systems, which combine advantage of NPs and solid dosage formulation, were designed, developed, and characterized demonstrating the possibility to obtaining oral administration. The resulting NPs were thus carried on oral dosage forms, i.e., pellets and minitablets. NPs resulted stable after dosage forms manufacturing, leading to confidence also on protection of encapsulated drugs. Indomethacin was used as a tracer to test biopharmaceutical behaviour.Anti-inflammatories or cytotoxic chemotherapeutics could be vehiculated leading to a breakthrough in the treatment of severe diseases allowing the oral administration of these drugs. We believe that the advancement achieved with the results of our work paves the way for the progression of nanoproducts into clinical transition processes.

Mint3-depletion-induced energy stress sensitizes triple-negative breast cancer to chemotherapy via HSF1 inactivation

Given the lack of therapeutic targets, the conventional approach for managing triple-negative breast cancer (TNBC) involves the utilization of cytotoxic chemotherapeutic agents. However, most TNBCs acquire resistance to chemotherapy, thereby lowering the therapeutic outcome. In addition to oncogenic mutations in TNBC, microenvironment-induced mechanisms render chemoresistance more complex and robust in vivo. Here, we aimed to analyze whether depletion of Munc18-1 interacting protein 3 (Mint3), which activates hypoxia-inducible factor 1 (HIF-1) during normoxia, sensitizes TNBC to chemotherapy. We found that Mint3 promotes the chemoresistance of TNBC in vivo. Mint3 depletion did not affect the sensitivity of human TNBC cell lines to doxorubicin and paclitaxel in vitro but sensitized tumors of these cells to chemotherapy in vivo. Transcriptome analyses revealed that the Mint3–HIF-1 axis enhanced heat shock protein 70 (HSP70) expression in tumors of TNBC cells. Administering an HSP70 inhibitor enhanced the antitumor activity of doxorubicin in TNBC tumors, similar to Mint3 depletion. Mint3 expression was also correlated with HSP70 expression in human TNBC specimens. Mechanistically, Mint3 depletion induces glycolytic maladaptation to the tumor microenvironment in TNBC tumors, resulting in energy stress. This energy stress by Mint3 depletion inactivated heat shock factor 1 (HSF-1), the master regulator of HSP expression, via the AMP-activated protein kinase/mechanistic target of the rapamycin pathway following attenuated HSP70 expression. In conclusion, Mint3 is a unique regulator of TNBC chemoresistance in vivo via metabolic adaptation to the tumor microenvironment, and a combination of Mint3 inhibition and chemotherapy may be a good strategy for TNBC treatment.