Search Results (1,316)

The concept of “platinum sensitivity” has long guided prognostic assessment and treatment selection in recurrent ovarian cancer. However, the emergence of targeted agents, such as bevacizumab and poly (ADP-ribose) polymerase inhibitors, has complicated its clinical utility. In contrast, emerging evidence suggests that platinum sensitivity may also be applicable to recurrent endometrial cancer. As in ovarian cancer, a prolonged platinum-free interval (PFI) in recurrent endometrial cancer is associated with an improved efficacy of subsequent platinum-based chemotherapy. The PFI is linearly correlated with the response rate to platinum re-administration, progression-free survival, and overall survival. Patients are typically classified as having platinum-resistant or platinum-sensitive disease based on a PFI cutoff of 6 or 12 months. However, unlike in ovarian cancer—where the duration of response to second-line platinum-based chemotherapy rarely exceeds the prior PFI (~3%)—approximately 30% of patients with recurrent endometrial cancer exhibit a sustained response to platinum rechallenge that extends beyond their preceding PFI. Despite the incorporation of immune checkpoint inhibitors into the treatment landscape of endometrial cancer, the role of platinum sensitivity in clinical decision-making—particularly regarding treatment sequencing and drug selection—remains a critical and unresolved issue. Further research is warranted to elucidate the mechanisms underlying platinum resistance and to guide optimal therapeutic strategies. Full article

The ATP-binding cassette transporter ABCG2 plays a critical role in drug pharmacokinetics and multidrug resistance in cancer therapy. Two common nonsynonymous polymorphisms, rs2231137 (V12M) and rs2231142 (Q141K), are associated with altered ABCG2 function, drug response, and disease susceptibility. However, the functional impact of their haplotype remains poorly understood. In this study, we established Flp-In™-293 cell lines stably expressing ABCG2 (12M/141K) and systematically compared their expression and drug resistance profiles with those of cells expressing ABCG2 (12V/141Q) (WT), ABCG2 (12M/141Q), and ABCG2 (12V/141K). The mRNA of ABCG2 (12M/141K) was expressed at levels comparable to those of the other variants in cells. Cells expressing ABCG2 (12M/141K) exhibited significantly higher resistance to mitoxantrone (10.7-fold) and SN-38 (5.99-fold) than the mock cells. While ABCG2 (12M/141Q) conferred the highest resistance among the tested variants, the ABCG2 (12M/141K) haplotype showed a trend toward higher mitoxantrone resistance than the ABCG2 (12V/141Q) (WT) (p = 0.066), suggesting a haplotype-specific effect. These findings provide novel insights into haplotype-based modulation of ABCG2 function and its contribution to multidrug resistance, with potential implications for optimizing personalized chemotherapy strategies. Full article

DNA damage repair is a hallmark of any cancer growth, eventually leading to drug resistance and death. The poly ADP-ribose polymerase (PARP) enzyme is vital in repairing damaged DNA in normal and cancer cells with mutated DNA damage response (DDR) genes. Inhibitors of the PARP enzyme aid in chemotherapy, as shown by drug combinations such as Olaparib and Irinotecan in breast cancer treatment. However, the effect of Olaparib in colon cancer has not been studied extensively. Synthetic drugs have a significant limitation in cancer treatment due to drug resistance, leading to colon cancer relapse. Bioavailability of Olaparib and other PARP inhibitors is limited due to their hydrophobicity, which poses a significant challenge. These limitations and challenges can be addressed by encapsulating Olaparib in nanoparticles that could possibly increase the bioavailability of the drug at the site of action. New age nanoparticles, such as hybrid nanoparticles, provide superior quality in terms of design and circulatory time of the drug in the plasma. The side effects of Olaparib as a chemotherapeutic pave the way for exploring phytochemicals that may have similar effects. The combined impact of Olaparib and phytochemicals such as genistein, resveratrol and others in nano-encapsulated form can be explored in the treatment of colon cancer. Full article

Background/Objectives: Upper tract urothelial carcinoma (UTUC) is a rare and biologically distinct subset of urothelial malignancies, comprising approximately 5–10% of urothelial cancers. UTUC presents unique diagnostic and therapeutic challenges, with both a higher likelihood of invasive disease at presentation and a less favorable prognosis compared to urothelial carcinoma of the bladder. Current treatment strategies for UTUC are largely derived from bladder cancer studies, underscoring the need for UTUC-directed research. This review provides a comprehensive overview of UTUC, encompassing diagnostic approaches, systemic and intraluminal therapies, surgical management, and future directions. Methods: A narrative review was conducted synthesizing evidence from guideline-based recommendations, retrospective and prospective clinical studies, and ongoing trials focused on UTUC. Results: Neoadjuvant cisplatin-based chemotherapy is increasingly preferred in UTUC due to the risk of postoperative renal impairment that may preclude adjuvant cisplatin use. Surgical management includes kidney-sparing approaches and radical nephroureterectomy (RNU), with selection guided by tumor risk and patient comorbidities. While endoscopic management (EM) preserves renal function, it carries a higher recurrence and surveillance burden; RNU remains standard for high-risk cases. Systemic therapy for advanced and metastatic UTUC mirrors that of bladder urothelial carcinoma. Enfortumab vedotin (EV) plus pembrolizumab showed superior efficacy over chemotherapy in the EV-302 trial, with improved response rate, progression-free survival, and overall survival across subgroups, including UTUC. For patients ineligible for EV, the CheckMate-901 study supported first-line chemoimmunotherapy with gemcitabine, cisplatin, and nivolumab. Further systemic therapy strategies include maintenance avelumab post-chemotherapy (JAVELIN Bladder 100), targeted therapies such as erdafitinib (THOR trial), and trastuzumab deruxtecan (DESTINY-PanTumor02) in FGFR2/3-altered and HER2-positive disease, respectively. Conclusions: Historically, the therapeutic landscape of UTUC has been extrapolated from bladder cancer; however, ongoing research specific to UTUC is deriving more precise regimens involving the use of immune checkpoint inhibitors, antibody–drug conjugates, and biomarker-driven therapies. Full article

The tumor microenvironment plays an important role in tumor incidence, metastasis, and chemotherapy resistance. Novel therapeutic strategies targeting the tumor microenvironment have become a research focus in the field of biomedicine. In this study, we developed a smart small-molecule probe, TZ2, featuring pH/GSH dual-responsive characteristics. TZ2 exhibits a unique pH-dependent reaction mechanism: GSH is preferentially covalently modified with maleimide groups in acidic microenvironments (pH < 7), while specifically activating nucleophilic substitutions under alkaline conditions (pH > 7). It is worth noting that TZ2 effectively eliminates intracellular glutathione (GSH) in a time and concentration-dependent manner, demonstrating significant GSH depletion ability in various tumor cell lines. Pharmacodynamic studies have shown that TZ2 not only inhibits the cell cycle by regulating the expression of cell cycle-related proteins, but also effectively suppresses the cloning ability of cancer cells. Furthermore, TZ2 significantly increases the sensitivity of drug-resistant cancer cells to cisplatin. By integrating microenvironment modulation, real-time monitoring, and synergistic therapy, TZ2 provides a novel molecular tool and theoretical basis for tumor theranostics integration. Full article

Background/Objectives: Chemotherapy-induced alopecia is a common and distressing side effect of cancer treatment, significantly impacting patients’ psychological well-being. Nanocarriers offer a promising strategy for targeted drug delivery to hair follicles, while chitosan nanoparticles have demonstrated hair-growth-promoting properties. This study explores the potential of chitosan nanoparticles as a topical delivery system for five pharmacological agents—phenobarbital, pioglitazone, rifampicin, N-acetylcysteine, and tacrolimus—to prevent chemotherapy-induced alopecia. Methods: Drug-loaded chitosan nanoparticles were prepared using the ionic gelation technique and characterized by particle size, zeta potential, entrapment efficiency, FT-IR spectroscopy, and TEM imaging. Their efficacy was assessed in a cyclophosphamide-induced alopecia model in C57BL/6 mice through macroscopic observation, histopathological examination, and scanning electron microscopy of regrown hair. Results: The prepared particles were spherical, cationic, and between 205 and 536 nm in size. The entrapment efficiencies ranged from 8% to 63%. All five drugs mitigated follicular dystrophy, shifting the hair follicle response from dystrophic catagen to dystrophic anagen. Phenobarbital demonstrated the most significant hair regrowth and quality improvements, followed by N-acetyl cysteine and pioglitazone. Tacrolimus showed moderate efficacy, while rifampicin was the least effective. Conclusions: These findings suggest that phenobarbital-loaded chitosan nanoparticles represent a promising approach for the prevention and treatment of chemotherapy-induced alopecia, warranting further investigation for clinical applications. Full article

Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality, driven by chronic inflammation, gut microbiota dysbiosis, and complex tumor microenvironment interactions. Current therapies are limited by systemic toxicity and poor tumor accumulation. This study aimed to develop a ROS/enzyme dual-responsive oral drug delivery system, KGM-CUR/PSM microspheres, to achieve precise drug release in CRC and enhance tumor-specific drug accumulation, which leverages high ROS levels in CRC and the β-mannanase overexpression in colorectal tissues. Methods: In this study, we synthesized a ROS-responsive prodrug polymer (PSM) by conjugating polyethylene glycol monomethyl ether (mPEG) and mesalazine (MSL) via a thioether bond. CUR was then encapsulated into PSM using thin-film hydration to form tumor microenvironment-responsive micelles (CUR/PSM). Subsequently, konjac glucomannan (KGM) was employed to fabricate KGM-CUR/PSM microspheres, enabling targeted delivery for colorectal cancer therapy. The ROS/enzyme dual-response properties were confirmed through in vitro drug release studies. Cytotoxicity, cellular uptake, and cell migration were assessed in SW480 cells. In vivo efficacy was evaluated in AOM/DSS-induced CRC mice, monitoring tumor growth, inflammatory markers (TNF-α, IL-1β, IL-6, MPO), and gut microbiota composition. Results: In vitro drug release studies demonstrated that KGM-CUR/PSM microspheres exhibited ROS/enzyme-responsive release profiles. CUR/PSM micelles demonstrated significant anti-CRC efficacy in cytotoxicity assays, cellular uptake studies, and cell migration assays. In AOM/DSS-induced CRC mice, KGM-CUR/PSM microspheres significantly improved survival and inhibited CRC tumor growth, and effectively reduced the expression of inflammatory cytokines (TNF-α, IL-1β, IL-6) and myeloperoxidase (MPO). Histopathological and microbiological analyses revealed near-normal colon architecture and microbial diversity in the KGM-CUR/PSM group, confirming the system’s ability to disrupt the “inflammation-microbiota-tumor” axis. Conclusions: The KGM-CUR/PSM microspheres demonstrated a synergistic enhancement of anti-tumor efficacy by inducing apoptosis, alleviating inflammation, and modulating the intestinal microbiota, which offers a promising stimuli-responsive drug delivery system for future clinical treatment of CRC. Full article

Circular RNA (CircRNA) is a single-stranded RNA arising from back splicing. CircRNAs interact with mRNA, miRNA, and proteins. These interactions regulate various life processes, including transcription, translation, cancer progression, anticancer drug resistance, and metabolism. Due to a lack of cap and poly(A) tails, circRNAs show exceptional stability and resistance to RNase degradation. CircRNAs exhibit dysregulated expression patterns in various cancers and influence cancer progression. Stability and regulatory roles in cancer progression make circRNAs reliable biomarkers and targets for the development of anticancer therapeutics. The dysregulated expression of circRNAs is associated with resistance to anticancer drugs. Enhanced glycolysis by circRNAs leads to resistance to anticancer drugs. CircRNAs have been known to regulate the response to chemotherapy drugs and immune checkpoint inhibitors. Exogenous circRNAs can encode antigens that can induce both innate and adaptive immunity. CircRNA vaccines on lipid nanoparticles have been shown to enhance the sensitivity of cancer patients to immune checkpoint inhibitors. In this review, we summarize the roles and mechanisms of circRNAs in anticancer drug resistance and glycolysis. This review discusses clinical applications of circRNA vaccines to overcome anticancer drug resistance and enhance the efficacy of immune checkpoint inhibitors. The advantages and disadvantages of circRNA vaccines are also discussed. Overall, this review stresses the potential value of circRNAs as new therapeutic targets and diagnostic/prognostic biomarkers for cancer Full article

Increasing evidence demonstrates the mutualistic connection between the microbiome and acute myeloid leukemia (AML) treatment. Drugs disrupt the microbial balance and, conversely, changes in the microbiome influence therapy. A new field, pharmacomicrobiomics, examines the role of the microbiome in pharmacokinetics, pharmacodynamics, and drug toxicity. The multimodal therapeutic management of AML, along with disease-related immunosuppression, infection, and malnutrition, creates the unique microbial profile of AML patients, in which every delicate modification plays a crucial role in pharmacotherapy. While both preclinical and real-world data have confirmed a bilateral connection between standard chemotherapy and the microbiome, the impact of novel targeted therapies and immunotherapy remains unknown. Multi-omics technologies have provided qualitative and mechanistic insights into specific compositional and functional microbial signatures associated with the outcomes of AML therapy, but require a large-scale investigation to draw reliable conclusions. In this review, we outline the role of the microbiome within the therapeutic landscape of AML, focusing on the determinants of post-treatment dysbiosis and its effects on the therapeutic response and toxicity. We explore emerging strategies for microbiota modulation, highlighting their safety and efficacy. Advances in microbiome-based approaches are an inevitable step toward precision medicine in AML. However, clinical research in a well-defined group of immunocompromised patients is needed to study their variable effects on human health and determine safety issues. Full article

Background/Objectives: PEGylated liposomes are widely recognized for their biocompatibility and capacity to extend systemic circulation via “stealth” properties. However, the PEG corona often limits tumor penetration and cellular internalization. Targeting matrix metalloproteinase-2 (MMP-2), frequently upregulated in breast cancer stroma, presents an opportunity to enhance tissue-specific drug delivery. In this study, we engineered MMP-2-responsive GPLGVRG peptide-modified cleavable PEGylated liposomes for targeted paclitaxel (PTX) delivery. Methods: Molecular docking simulations employed the MMP-2 crystal structure (PDB ID: 7XJO) to assess GPLGVRG peptide binding affinity. A cleavable, enzyme-sensitive peptide-PEG conjugate (Chol-PEG_2K-GPLGVRG-PEG_5K) was synthesized via small-molecule liquid-phase synthesis and characterized by ¹H NMR and MALDI-TOF MS. Liposomes incorporating this conjugate (S-Peps-PEG_5K) were formulated to evaluate whether MMP-2-mediated peptide degradation triggers detachment of long-chain PEG moieties, thereby enhancing internalization by 4T1 breast cancer cells. Additionally, the effects of tumor microenvironmental pH (~6.5) and MMP-2 concentration on drug release dynamics were investigated. Results: Molecular docking revealed robust GPLGVRG-MMP-2 interactions, yielding a binding energy of −7.1 kcal/mol. The peptide formed hydrogen bonds with MMP-2 residues Tyr A:23 and Arg A:53 (bond lengths: 2.4–2.5 Å) and engaged in hydrophobic contacts, confirming MMP-2 as the primary recognition site. Formulations containing 5 mol% Chol-PEG_2K-GPLGVRG-PEG_5K combined with 0.15 µg/mL MMP-2 (S-Peps-PEG_5K +MMP) exhibited superior internalization efficiency and significantly reduced clonogenic survival compared to controls. Notably, acidic pH (~6.5) induced MMP-2-mediated cleavage of the GPLGVRG peptide, accelerating S-Peps-PEG_5K dissociation and facilitating drug release. Conclusions: MMP-2-responsive, cleavable PEGylated liposomes markedly improve PTX accumulation and controlled release at tumor sites by dynamically modulating their stealth properties, offering a promising strategy to enhance chemotherapy efficacy in breast cancer. Full article

Autophagy-dependent cell death (ADCD) presents a promising but challenging therapeutic strategy in cancer treatment. Autophagy regulates cellular breakdown and stress responses, serving a dual function—either inhibiting tumorigenesis or facilitating the survival of cancer cells in advanced stages. This paradox presents both opportunities and challenges in the exploration of autophagy as a potential target for cancer treatment. In this review, we explore various pharmacological agents, including autophagy inhibitors (e.g., chloroquine, 3-MA) and activators (e.g., rapamycin, metformin), which have demonstrated effectiveness in modulating autophagy-dependent cell death (ADCD). These agents either enhance cancer cell apoptosis or sensitize tumors to conventional therapies. Combination therapies, such as the use of autophagy modulators alongside chemotherapy, immunotherapy, or radiation therapy, offer enhanced therapeutic potential by overcoming drug resistance and improving overall treatment efficacy. Nonetheless, significant challenges remain, including tumor heterogeneity, treatment resistance, and off-target effects of autophagy-targeting agents. Future progress in biomarker discovery, precision medicine, and targeted medication development will be crucial for enhancing ADCD-based methods. Although autophagy-dependent cell death presents significant potential in cancer treatment, additional studies and clinical validation are necessary to confirm its position as a conventional therapeutic approach. Therefore, this review aims to identify the existing restrictions that will facilitate the development of more effective and personalized cancer therapies, hence enhancing patient survival and outcomes. Full article

Nucleobase and nucleoside analogs are critical components of antimetabolite chemotherapy treatments used to disrupt DNA replication and induce apoptosis in rapidly proliferating cancer cells. However, the development of resistance to these agents remains a major clinical challenge. This review explores the epigenetic mechanisms that contribute to acquired chemoresistance, focusing on DNA methylation, histone modifications, and non-coding RNAs (ncRNAs). These epigenetic alterations regulate key processes such as DNA repair, drug metabolism, cell transport, and autophagy, enabling cancer cells to survive and resist therapeutic pressure. We highlight how dysregulation of DNA methyltransferases (DNMTs) and histone acetyltransferases (HATs) modulates expression of transporters (e.g., hENT1, ABCB1), DNA repair enzymes (e.g., Polβ, BRCA1/2), and autophagy-related genes (e.g., CSNK2A1, BNIP3). Furthermore, emerging roles for long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in regulating nucleoside export and DNA damage response pathways underscore their relevance as therapeutic targets. The interplay of these epigenetic modifications drives resistance to agents such as gemcitabine and 5-fluorouracil across multiple tumor types. We also discuss recent progress in therapeutic interventions, including DNMT and HDAC inhibitors, RNA-based therapeutics, and CRISPR-based epigenome editing. Full article

Despite remarkable advancements in cancer immunotherapy, its clinical efficacy remains constrained in solid tumors due to the immunosuppressive tumor microenvironment (TME). Reactive oxygen species (ROS), which exhibit dual regulatory roles in the TME by regulating immunogenic cell death (ICD) and reprogramming immune cell functionality, have emerged as a pivotal therapeutic target. Nano-enabled drug delivery systems present distinct advantages for TME modulation due to their structural versatility, tumor-specific targeting precision, and spatiotemporally controlled drug release. In particular, ROS-responsive nanoplatforms demonstrate multifaceted immunomodulatory potential by synergistically restoring ICD and remodeling immunosuppressive immune cell phenotypes within the TME. These platforms further amplify the therapeutic outcomes of conventional modalities including chemotherapy, radiotherapy, and photodynamic therapy (PDT) through ROS-mediated sensitization mechanisms. This review comprehensively examines recent breakthroughs in ROS-responsive nanosystems for antitumor immunotherapy, emphasizing their mechanistic interplay with TME components and clinical translation potential. Herein, we provide a framework for developing integrated therapeutic strategies to overcome the current limitations in cancer immunotherapy. Full article

Glioblastoma (GB) is the most common malignant primary CNS tumor with a fast-growing and invasive profile. As a result of the poor prognosis and limited therapy available, glioblastoma shows a high mortality rate. Given the scarcity of effective chemotherapy options, multiple studies have explored the potential of tyrosine kinase inhibitors. To mitigate resistance and improve potency and selectivity, we proposed the combination of a potent irreversible epidermal growth factor receptor inhibitor—LASSBio-1971—and a potent phosphatidylinositol-3-kinase/mammalian target of rapamycin dual inhibitor—Gedatolisib—through an in vitro phenotypic study using five human GB lines. Here, we aimed to establish the cytotoxic potency, selectivity, and effect on proliferation, apoptosis, migration, and the cell cycle. Our data showed the cytotoxic potency of Gedatolisib and LASSBio-1971 and improved selectivity in the GB cell lines. They highlighted the synergistic response from their combination and its impact on migration reduction, G0/G1 cell cycle arrest, GB cytotoxicity, and apoptosis-inducing effects for different GB cell lines. The drug combination studies in phenotypic in vitro models made it possible to suggest a new potential treatment for glioblastoma that justifies further safety in in vivo phases of preclinical trials with the combination. Full article

Despite the promising natural origin, biocompatibility, and biodegradability of chitosan for biomedical applications, developing biodegradable nanocarriers with controllable sizes and precise drug delivery targeting remains a significant challenge, hindering its integration into precision medicine. To address this, we synthesized gold nanocage (AuNCs)/poly-(N-isopropylacrylamide-co-carboxymethyl chitosan) core-shell multifunctional composite nanospheres (CPAu) through a two-step one-pot method. The resulting CPAu nanospheres (~146 nm in size) exhibited multi-sensitive release properties, excellent biocompatibility, and potent photothermal therapy (PTT) activity. These nanospheres effectively encapsulated diverse antitumor drugs while demonstrating triple responsiveness (thermo-, reduction-, and PTT-triggered) for targeted tumor cell delivery, thereby achieving enhanced antitumor efficacy in combinatorial chemotherapy. Full article