RESUMEN

Chemoimmunotherapy is an emerging paradigm in the clinic for treating several malignant diseases, such as non-small cell lung cancer, breast cancer, and large B-cell lymphoma. However, the efficacy of this strategy is still restricted by serious adverse events and a high therapeutic termination rate, presumably due to the lack of tumor-targeted distribution of both chemotherapeutic and immunotherapeutic agents. Targeted drug delivery has the potential to address this issue. Among the most promising nanocarriers in clinical translation, liposomes have drawn great attention in cancer chemoimmunotherapy in recent years. Liposomes-enabled cancer chemoimmunotherapy has made significant progress in clinics, with impressive therapeutic outcomes. This review summarizes the latest preclinical and clinical progress in liposome-enabled cancer chemoimmunotherapy and discusses the challenges and future directions of this field.

Asunto(s)

Inmunoterapia , Liposomas , Neoplasias , Liposomas/química , Humanos , Inmunoterapia/métodos , Animales , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Sistemas de Liberación de Medicamentos/métodos , Antineoplásicos/uso terapéutico , Antineoplásicos/administración & dosificación

RESUMEN

Copper (Cu), an essential micronutrient with redox properties, plays a pivotal role in a wide array of pathological and physiological processes across virtually all cell types. Maintaining an optimal copper concentration is critical for cellular survival: insufficient copper levels disrupt respiration and metabolism, while excess copper compromises cell viability, potentially leading to cell death. Similarly, in the context of cancer, copper exhibits a dual role: appropriate amount of copper can promote tumor progression and be an accomplice, yet beyond befitting level, copper can bring about multiple types of cell death, including autophagy, apoptosis, ferroptosis, immunogenic cell death, pyroptosis, and cuproptosis. These forms of cell death are beneficial against cancer progression; however, achieving precise copper regulation within tumors remains a significant challenge in the pursuit of effective cancer therapies. The emergence of nanodrug delivery systems, distinguished by their precise targeting, controlled release, high payload capacity, and the ability to co-deliver multiple agents, has revitalized interest in exploiting copper's precise regulatory capabilities. Nevertheless, there remains a dearth of comprehensive review of copper's bidirectional effects on tumorigenesis and the role of copper-based nanomaterials in modulating tumor progression. This paper aims to address this gap by elucidating the complex role in cancer biology and highlighting its potential as a therapeutic target. Through an exploration of copper's dualistic nature and the application of nanotechnology, this review seeks to offer novel insights and guide future research in advancing cancer treatment.

Asunto(s)

Cobre , Nanoestructuras , Neoplasias , Cobre/química , Humanos , Animales , Nanoestructuras/química , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neoplasias/metabolismo , Muerte Celular/efectos de los fármacos

RESUMEN

Ferroptosis, a recently identified form of cell death, holds promise for cancer therapy, but concerns persist regarding its uncontrolled actions and potential side effects. Here, we present a semiconducting polymer nanoprodrug (SPNpro) featuring an innovative ferroptosis prodrug (DHU-CBA7) to induce sono-activatable ferroptosis for tumor-specific therapy. DHU-CBA7 prodrug incorporate methylene blue, ferrocene and urea bond, which can selectively and specifically respond to singlet oxygen (1O2) to turn on ferroptosis action via rapidly cleaving the urea bonds. DHU-CBA7 prodrug and a semiconducting polymer are self-assembled with an amphiphilic polymer to construct SPNpro. Ultrasound irradiation of SPNpro leads to the production of 1O2 via sonodynamic therapy (SDT) of the semiconducting polymer, and the generated 1O2 activated DHU-CBA7 prodrug to achieve sono-activatable ferroptosis. Consequently, SPNpro combine SDT with the controlled ferroptosis to effectively cure 4T1 tumors covered by 2-cm tissue with a tumor inhibition efficacy as high as 100 %, and also completely restrain tumor metastases. This study introduces a novel sono-activatable prodrug strategy for regulating ferroptosis, allowing for precise cancer therapy.

Asunto(s)

Ferroptosis , Ratones Endogámicos BALB C , Polímeros , Profármacos , Semiconductores , Ferroptosis/efectos de los fármacos , Profármacos/farmacología , Profármacos/química , Profármacos/uso terapéutico , Animales , Polímeros/química , Femenino , Línea Celular Tumoral , Ratones , Terapia por Ultrasonido/métodos , Nanopartículas/química , Humanos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Oxígeno Singlete/metabolismo

RESUMEN

Photodynamic therapy (PDT) and sonodynamic therapy (SDT), using nonionizing light and ultrasound to generate reactive oxygen species, offer promising localized treatments for cancers. However, the effectiveness of PDT is hampered by inadequate tissue penetration, and SDT largely relies on pyrolysis and sonoluminescence, which may cause tissue injury and imprecise targeting. To address these issues, we have proposed a mechanochemical dynamic therapy (MDT) that uses free radicals generated from mechanophore-embedded polymers under mechanical stress to produce reactive oxygen species for cancer treatment. Yet, their application in vivo is constrained by the bulk form of the polymer and the need for high ultrasound intensities for activation. In this study, we developed injectable, nanoscale mechanophore particles with enhanced ultrasound sensitivity by leveraging a core-shell structure comprising silica nanoparticles (NPs) whose interfaces are linked to polymer brushes by an azo mechanophore moiety. Upon focused ultrasound (FUS) treatment, this injectable NP generates reactive oxygen species (ROS), demonstrating promising results in both an in vitro 4T1 cell model and an in vivo mouse model of orthotopic breast cancers. This research offers an alternative therapy technique, integrating force-responsive azo mechanophores and FUS under biocompatible conditions.

RESUMEN

The combination of anti-angiogenic drugs and immune checkpoint inhibitors (ICIs) in the treatment of tumors is emerging as a way to improve ICIs-resistant tumor therapy. In addition, gut microbes (GMs) are involved in angiogenesis in the tumor microenvironment and are also associated with the antitumor function of immune checkpoint inhibitors. However, it is unclear whether gut microbes have a role in anti-tumor function in the combination of anti-angiogenic drugs and immune checkpoint inhibitors for cancer treatment. Endostatin, an angiogenesis inhibitor, has been widely used as an antiangiogenic therapy for cancer. We showed that combined therapy with an adenovirus encoding human endostatin, named Ad-E, and PD-1 blockade dramatically abrogated MC38 tumor growth. The structure of intestinal microbes in mice was changed after combination treatment. We found that the antitumor function of combination therapy was inhibited after the elimination of intestinal microbes. In mice with depleted microbiota, oral gavage of Bacteroides fragilis salvaged the antitumor effects of combination Ad-E and αPD-1 monoclonal antibody (mAb) to a certain extent. Further, Bacteroides fragilis could improve CD3+T cells, NK cells, and IFNγ+CD8+ T cells in the tumor microenvironment to inhibit tumor growth. Besides, Bacteroides fragilis might restore antitumor function by down-regulating isobutyric acid (IBA). Our results suggested that GMs may be involved in the combination of Ad-E and αPD-1 mAb for cancer treatment, which has oncological implications for tumor growth dynamics and cancer immune surveillance.

Asunto(s)

Neoplasias Colorrectales , Endostatinas , Microbioma Gastrointestinal , Inhibidores de Puntos de Control Inmunológico , Receptor de Muerte Celular Programada 1 , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Endostatinas/farmacología , Endostatinas/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/microbiología , Neoplasias Colorrectales/patología , Ratones , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Humanos , Línea Celular Tumoral , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Ratones Endogámicos C57BL , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de la Angiogénesis/administración & dosificación , Femenino

RESUMEN

Anaplastic thyroid carcinoma (ATC) is the most aggressive thyroid cancer, and it has a poor prognosis and high probability of metastatic recurrence. The long-term survival of cancer cells depends on their ability to settle in a favorable environment. Cancer cells interact with other cells in the tumor microenvironment to shape the "soil" and make it suitable for cell growth by forming an extremely complex tumor ecosystem. The extracellular matrix (ECM) is an essential component of the tumor ecosystem, and its biological and mechanical changes strongly affect tumor invasion, metastasis, immune escape and drug resistance. Compared to normal tissues, biological processes, such as collagen synthesis and ECM signaling, are significantly activated in ATC tissues. However, how ATC triggers changes in the properties of the ECM and its interaction with the ECM remain poorly characterized. Therefore, an in-depth study of the regulatory mechanism of the abnormal activation of ECM signaling in ATC is highly important for achieving the therapeutic goal of exerting antitumor effects by destroying the "soil" in which cancer cells depend for survival. In this research, we revealed the aberrant activation state of ECM signaling in ATC progression and attempted to uncover the potential mechanism of action of ECM components in ATC, with the aim of providing new drug targets for ATC therapy.

Asunto(s)

Matriz Extracelular , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Microambiente Tumoral , Carcinoma Anaplásico de Tiroides/patología , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Carcinoma Anaplásico de Tiroides/metabolismo , Humanos , Matriz Extracelular/metabolismo , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/metabolismo , Transducción de Señal

RESUMEN

The human adenovirus (HADV) early region 4 open reading frame 4 (E4orf4) protein plays a regulatory role in promoting viral infection by interacting with various cellular proteins. E4orf4 can induce death in cancer cells. One of the death pathways that is induced by this protein is related to the formation of membrane blebbing following the phosphorylation of tyrosine amino acids. The activation of this pathway requires the interaction of E4orf4 with Src family kinases (SFKs). The modulation mechanism of Src-dependent signaling via E4orf4 is not yet fully understood. However, evidence suggests that a physical association between the Src kinase domain and the arginine-rich motif of E4orf4 is crucial. Physically connecting E4orf4 to Src kinase leads to the deregulation of the Src-related signaling pathway, thereby inducing cytoplasmic death. In this study, we mapped the E4orf4 interaction site in Src to investigate the interaction between E4orf4 and Src in detail. We also compared the binding strength of E4orf4 proteins from different HADV groups. To this end, we performed bioinformatics structural analysis of the Src kinase domain and E4orf4 to identify E4orf4 interaction sites. The group with the lowest binding energy was predicted to be the most likely candidate for the highest cytoplasmic death in tumor cells based on the energy of the E4orf4-Src complex in various HADV groups. These results show that HADV-A and HADV-C have minimal binding energies to the E4orf4-Src complex, while the dissociation constant (Kd) of HADV-A was less than that of HADV-C. According to the obtained results, E4orf4 of the HADV-A group is more effective at triggering cytoplasmic death based on its most robust interaction with the Src kinase domain.

RESUMEN

Programmed death-ligand 1 (PD-L1) on tumor-derived small extracellular vesicles (sEVs) limits therapeutic effectiveness by interacting with the PD-1 receptor on host immune cells. Targeting the secretion of sEV PD-L1 has emerged as a promising strategy to enhance immunotherapy. However, the lack of small-molecule inhibitors poses a challenge for clinical translation. In this study, we developed a target and phenotype dual-driven high-throughput screening strategy that combined virtual screening with nanoflow-based experimental verification. We identified ibuprofen (IBP) as a novel inhibitor that effectively targeted sEV PD-L1 secretion. IBP disrupted the biogenesis and secretion of PD-L1+ sEVs in tumor cells by physically interacting with a critical regulator of sEV biogenesis, hepatocyte growth factor-regulated tyrosine kinase substrate. Notably, the mechanism of action of IBP is distinct from its commonly known targets, cyclooxygenases. Administration of IBP stimulated antitumor immunity and enhanced the efficacy of anti-PD-1 therapy in melanoma and oral squamous cell carcinoma mouse models. To address potential adverse effects, we further developed an IBP gel for topical application, which demonstrated remarkable therapeutic efficacy when combined with anti-PD-1 treatment. The discovery of this specific small inhibitor provides a promising avenue for establishing durable, systemic antitumor immunity.

RESUMEN

Advancements in our comprehension of tumor biology and chemoresistance have spurred the development of treatments that precisely target specific molecules within the body. Despite the expanding landscape of therapeutic options, there persists a demand for innovative approaches to address unmet clinical needs. RNA therapeutics have emerged as a promising frontier in this realm, offering novel avenues for intervention such as RNA interference and the utilization of antisense oligonucleotides (ASOs). ASOs represent a versatile class of therapeutics capable of selectively targeting messenger RNAs (mRNAs) and silencing disease-associated proteins, thereby disrupting pathogenic processes at the molecular level. Recent advancements in chemical modification and carrier molecule design have significantly enhanced the stability, biodistribution, and intracellular uptake of ASOs, thereby bolstering their therapeutic potential. While ASO therapy holds promise across various disease domains, including oncology, coronary angioplasty, neurological disorders, viral, and parasitic diseases, our review manuscript focuses specifically on the application of ASOs in targeted cancer therapies. Through a comprehensive examination of the latest research findings and clinical developments, we delve into the intricacies of ASO-based approaches to cancer treatment, shedding light on their mechanisms of action, therapeutic efficacy, and prospects.

RESUMEN

The search for new antineoplastic agents is imperative, as cancer remains one of the most preeminent causes of death worldwide. Since the discovery of the therapeutic potential of cisplatin, the study of metallodrugs in cancer chemotherapy acquired increasing interest. Starting from cisplatin derivatives, such as oxaliplatin and carboplatin, in the last years, different compounds were explored, employing different metal centers such as iron, ruthenium, gold, and palladium. Nonetheless, metallodrugs face several drawbacks, such as low water solubility, rapid clearance, and possible side toxicity. Encapsulation has emerged as a promising strategy to overcome these issues, providing both improved biocompatibility and protection of the payload from possible degradation in the biological environment. In this respect, liposomes, which are spherical vesicles characterized by an aqueous core surrounded by lipid bilayers, have proven to be ideal candidates due to their versatility. In fact, they can encapsulate both hydrophilic and hydrophobic drugs, are biocompatible, and their properties can be tuned to improve the selective delivery to tumour sites exploiting both passive and active targeting. In this review, we report the most recent findings on liposomal formulations of metallodrugs, with a focus on encapsulation techniques and the obtained biological results.

Asunto(s)

Antineoplásicos , Liposomas , Neoplasias , Liposomas/química , Humanos , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Antineoplásicos/administración & dosificación , Neoplasias/tratamiento farmacológico , Animales , Composición de Medicamentos , Sistemas de Liberación de Medicamentos/métodos

RESUMEN

Natural products have proven to be promising anti-cancer agents due to their diverse chemical structures and bioactivity. This review examines their central role in cancer treatment, focusing on their mechanisms of action and therapeutic benefits. Medicinal plants contain bioactive compounds, such as flavonoids, alkaloids, terpenoids and polyphenols, which exhibit various anticancer properties. These compounds induce apoptosis, inhibit cell proliferation and cell cycle progression, interfere with microtubule formation, act on topoisomerase targets, inhibit angiogenesis, modulate key signaling pathways, improve the tumor microenvironment, reverse drug resistance and activate immune cells. Herbal anti-cancer drugs offer therapeutic advantages, particularly selective toxicity against cancer cells, reducing the adverse side effects associated with conventional chemotherapy. Recent studies and clinical trials highlight the benefits of herbal medicines in alleviating side effects, improving tolerance to chemotherapy and the occurrence of synergistic effects with conventional treatments. For example, the herbal medicine SH003 was found to be safe and potentially effective in the treatment of solid cancers, while Fucoidan showed anti-inflammatory properties that are beneficial for patients with advanced cancer. The current research landscape on herbal anticancer agents is extensive. Numerous studies and clinical trials are investigating their efficacy, safety and mechanisms of action in various cancers such as lung, prostate, breast and hepatocellular carcinoma. Promising developments include the polypharmacological approach, combination therapies, immunomodulation and the improvement of quality of life. However, there are still challenges in the development and use of natural products as anti-cancer drugs, such as the need for further research into their mechanisms of action, possible drug interactions and optimal dosage. Standardizing herbal extracts, improving bioavailability and delivery, and overcoming regulatory and acceptance hurdles are critical issues that need to be addressed. Nonetheless, the promising anticancer effects and therapeutic benefits of natural products warrant further investigation and development. Multidisciplinary collaboration is essential to advance herbal cancer therapy and integrate these agents into mainstream cancer treatment.

RESUMEN

With the continuous refinement of therapeutic measures, the survival rate of tumor patients has been improving year by year, while cardiovascular complications related to cancer therapy have become increasingly prominent. Exploring the mechanism and prevention strategy of cancer therapy-related cardiovascular toxicity (CTR-CVT) remains one of the research hotspots in the field of Cardio-Oncology in recent years. Cardiotoxicity of anticancer drugs involves heart failure, myocarditis, hypertension, arrhythmias and vascular toxicity, mechanistically related to vascular endothelial dysfunction, ferroptosis, mitochondrial dysfunction and oxidative stress. To address the cardiotoxicity induced by different anticancer drugs, various therapeutic measures have been put in place, such as reducing the accumulation of anticancer drugs, shifting to drugs with less cardiotoxicity, using cardioprotective drugs, and early detection. Due to the very limited treatments available to ameliorate anticancer drugs-induced cardiotoxicity, a few innovations are being shifted from animal studies to human studies. Examples include mitochondrial transplantation. Mitochondrial transplantation has been proven to be effective in in vivo and in vitro experiments. Several recent studies have demonstrated that intercellular mitochondrial transfer can ameliorate doxorubicin(DOX)-induced cardiotoxicity, laying the foundation for innovative therapies in anticancer drugs-induced cardiotoxicity. In this review, we will discuss the current status of anticancer drugs-induced cardiotoxicity in terms of the pathogenesis and treatment, with a focus on mitochondrial transplantation, and we hope that this review will bring some inspiration to you.

Asunto(s)

Antineoplásicos , Cardiotoxicidad , Humanos , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Animales , Neoplasias/tratamiento farmacológico

RESUMEN

Cancer, a complex and multifaceted group of diseases, continues to challenge the boundaries of medical science and healthcare. Its relentless impact on global health, both in terms of prevalence and mortality, underscores the urgent need for a comprehensive understanding of its underlying mechanisms and innovative therapeutic approaches. In recent years, significant progress has been achieved in identifying the genetic and epigenetic mechanisms that cause cancer development and treatment resistance. Researchers are currently investigating the possibility of epigenetic editing such as CRISPR-dCas9 (Clustered Regularly Interspaced Short Palindromic Repeats/deactivated CRISPR-associated protein 9) technologies, for targeting and modifying cancer related epigenetic alterations. A revolutionary form of precision cancer treatment called CRISPR-dCas9 is derived from the bacterial CRISPR-Cas (CRISPR-associated nuclease) system. CRISPR-dCas9 can be combined with epigenetic effectors (EE) to alter malignant epigenetic characteristics associated with cancer. The purpose of this review article is to provide a thorough analysis of recent advancements in utilizing CRISPR-dCas9 technology to target and modify epigenetic changes associated with cancer. This review aims to summarize the latest research developments, evaluate the effectiveness and limitations of CRISPR-dCas9 applications in cancer therapy, identify key challenges such as delivery methods and explore future directions for improving and expanding these technologies. Here, we address the various obstacles that may arise in clinical applications while showcasing the latest advancements and potential future uses of CRISPR-Cas9 in cancer therapy.

Asunto(s)

Sistemas CRISPR-Cas , Epigénesis Genética , Edición Génica , Neoplasias , Humanos , Neoplasias/genética , Neoplasias/terapia , Edición Génica/métodos , Animales

RESUMEN

Drug resistance remains a critical barrier in cancer therapy, diminishing the effectiveness of chemotherapeutic, targeted, and immunotherapeutic agents. Overexpression of proteins such as B-cell lymphoma 2 (Bcl-2), inhibitor of apoptosis proteins (IAPs), protein kinase B (Akt), and P-glycoprotein (P-gp) in various cancers leads to resistance by inhibiting apoptosis, enhancing cell survival, and expelling drugs. Although several inhibitors targeting these proteins have been developed, their clinical use is often hampered by systemic toxicity, poor bioavailability, and resistance development. Nanoparticle-based drug delivery systems present a promising solution by improving drug solubility, stability, and targeted delivery. These systems leverage the Enhanced Permeation and Retention (EPR) effect to accumulate in tumor tissues, reducing off-target toxicity and increasing therapeutic efficacy. Co-encapsulation strategies involving anticancer drugs and resistance inhibitors within nanoparticles have shown potential in achieving coordinated pharmacokinetic and pharmacodynamic profiles. This review discusses the mechanisms of drug resistance, the limitations of current inhibitors, and the advantages of nanoparticle delivery systems in overcoming these challenges. By advancing these technologies, we can enhance treatment outcomes and move towards more effective cancer therapies.

Asunto(s)

Antineoplásicos , Resistencia a Antineoplásicos , Nanopartículas , Neoplasias , Humanos , Resistencia a Antineoplásicos/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Nanopartículas/química , Animales , Sistemas de Liberación de Medicamentos

RESUMEN

Edible mushrooms are not only a valued culinary ingredient but also have several potential medicinal and industrial applications. They are a rich source of protein, fiber, vitamins, minerals, and bioactive compounds such as polysaccharides and terpenoids, and thus have the capacity to support human health. Some species have been shown to have antioxidant, anti-inflammatory, anticancer, and immunomodulatory properties. We have therefore attempted to summarize the potential properties of the edible mushrooms popular in Poland, in the Roztocze area.

Asunto(s)

Agaricales , Antineoplásicos , Antioxidantes , Polonia , Humanos , Agaricales/química , Antioxidantes/análisis , Antioxidantes/farmacología , Antineoplásicos/farmacología , Neoplasias , Antiinflamatorios/farmacología

RESUMEN

Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) play a pivotal role in regulating kynurenine catabolism pathway and immunosuppressive environment, which are promising drug targets for cancer immunotherapy. In this work, a variety of isoquinoline derivatives were designed, synthesized and evaluated for the inhibitory activity against IDO1 and TDO. The enzymatic assay and structure-activity relationship studies led to the most potent compound 43b with IC50 values of 0.31 µM for IDO1 and 0.08 µM for TDO, respectively. Surface plasmon resonance (SPR) revealed direct binding affinity of compound 43b to IDO1 and TDO and molecular docking studies were performed to predict the possible binding mode. Further pharmacokinetic study and biological evaluation in vivo showed that 43b displayed acceptable pharmacokinetic profiles and potent antitumor efficacy with low toxicity in B16-F10 tumor model, which might provide some insights into the discovery of novel IDO1/TDO inhibitors for cancer immunotherapy.

RESUMEN

BACKGROUND: For angioimmunoblastic T cell lymphoma (AITL), a rare cancer, no specific treatments are available and survival outcome is poor. We previously developed a murine model for AITL that mimics closely human disease and allows to evaluate new treatments. As in human AITL, the murine CD4+ follicular helper T (Tfh) cells are drivers of the malignancy. Therefore, chimeric antigen receptor (CAR) T cell therapy might represent a new therapeutic option. METHODS: To prevent fratricide among CAR T cells when delivering an CD4-specific CAR, we used a lentiviral vector (LV) encoding an anti-CD4 CAR, allowing exclusive entry into CD8 T cells. RESULTS: These anti-CD4CAR CD8-targeted LVs achieved in murine AITL biopsies high CAR-expression levels in CD8 T cells. Malignant CD4 Tfh cells were eliminated from the mAITL lymphoma, while the CAR + CD8 T cells expanded upon encounter with the CD4 receptor and were shaped into functional cytotoxic cells. Finally, in vivo injection of the CAR + CD8-LVs into our preclinical AITL mouse model carrying lymphomas, significantly prolonged mice survival. Moreover, the in vivo generated functional CAR + CD8 T cells efficiently reduced neoplastic T cell numbers in the mAITL tumors. CONCLUSION: This is the first description of in vivo generated CAR T cells for therapy of a T cell lymphoma. The strategy described offers a new therapeutic concept for patients suffering from CD4-driven T cell lymphomas.

Asunto(s)

Modelos Animales de Enfermedad , Inmunoterapia Adoptiva , Linfoma de Células T , Receptores Quiméricos de Antígenos , Animales , Ratones , Humanos , Receptores Quiméricos de Antígenos/inmunología , Inmunoterapia Adoptiva/métodos , Linfoma de Células T/terapia , Linfoma de Células T/inmunología , Linfoma de Células T/patología , Linfadenopatía Inmunoblástica/terapia , Linfadenopatía Inmunoblástica/inmunología , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral

RESUMEN

(1) Background: Cytoreductive surgery (CRS) with HIPEC is considered the standard of care for selected patients with peritoneal carcinomatosis, but evidence-based treatment recommendations for the therapy of peritoneal sarcomatosis are scarce. (2) Methods: We retrospectively analyzed all adult patients treated with CRS and HIPEC for peritoneal sarcomatosis between 2017 and 2024. (3) Results: Ten patients with a median age of 46.1 years (range: 23-77 years) with metachronous (40%) or synchronous (60%) peritoneal sarcomatosis from six different tumor entities were treated according to tumor board recommendation using CRS and HIPEC with cisplatin and doxorubicin over 60 min at 42.0 °C. The length of stay in the intensive care unit and hospital was 1.24 (0.6-1.9 days) and 11.1 days (6-17 days), respectively. Complete cytoreduction was achieved in 90% of the patients, with a median PSI of 11.5. Postoperative complications occurred in five cases, but no surgical revisions were necessary, and no acute kidney damage was recorded. (4) Conclusions: CRS with HIPEC in the presence of peritoneal sarcomatosis could be safely performed in our collective. Whether this resulted in an oncological treatment benefit cannot be concluded in view of the heterogeneous and small collective. Therefore, larger and prospective studies are warranted.

RESUMEN

Drug resistance has compromised the efficacy of chemotherapy. The dysregulation of drug transporters including P-glycoprotein (P-gp) can mediate drug resistance through drug efflux. In this review, we highlight the role of P-gp in cancer drug resistance and the related molecular pathways, including phosphoinositide 3-kinase (PI3K)-Akt, phosphatase and tensin homolog (PTEN) and nuclear factor-κB (NF-κB), along with non-coding RNAs (ncRNAs). Extracellular vesicles secreted by the cells can transport ncRNAs and other proteins to change P-gp activity in cancer drug resistance. P-gp requires ATP to function, and the induction of mitochondrial dysfunction or inhibition of glutamine metabolism can impair P-gp function, thus increasing chemosensitivity. Phytochemicals, small molecules and nanoparticles have been introduced as P-gp inhibitors to increase drug sensitivity in human cancers.