The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified and studied in the regulation of glycogen synthesis. In some cases, suppression of GSK-3 activity by phosphorylation by Akt and other kinases has been associated with cancer progression. In these cases, GSK-3 has tumor suppressor functions. In other cases, GSK-3 has been associated with tumor progression by stabilizing components of the beta-catenin complex. In these situations, GSK-3 has oncogenic properties. The Raf kinase inhibitor protein (RKIP) has been reported to be under expressed in many cancers and plays a role in the regulation of tumor cells' survival, proliferation, invasion, and metastasis, hence, a tumor suppressor. RKIP also regulates tumor cell resistance to cytotoxic drugs/cells. Likewise, the tumor suppressor, phosphatase and tensin homolog (PTEN), which inhibits the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) pathway, is either mutated, under expressed, or deleted in many cancers and shares with RKIP its anti-tumor properties and its regulation in resistance. Several pathways are regulated by RKIP, GSK-3, PTEN, and the transcriptional and post-transcriptional regulations of RKIP, GSK-3, and PTEN are significantly altered in cancers. In addition, RKIP, GSK-3 and PTEN play a key role in the regulation of tumor cells response to chemotherapy and immunotherapy. In this review, we will focus on the roles that GSK-3, PTEN, and RKIP play in various human cancers. We will also discuss how this pivotal kinase interacts with multiple signaling pathways such as: PI3K/PTEN/Akt/mechanistic target of rapamycin complex 1 (mTORC1), nuclear Factor kappa-B (NF-κB)/Snail family transcriptional repressor 1 (Snail)/Yin Yang 1 (YY1) loop, and rat sarcoma virus oncogene (Ras)/rapidly accelerated fibrosarcoma (Raf)/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK).

The regimen of rituximab we not determined based on evidence from pharmacokinetics. However, rituximab exhibited significant pharmacokinetic variability among different clinical populations, which might be a key factor influencing individual exposure and response to this monoclonal antibody. This systematic review aimed to analyze the traditional and population pharmacokinetics of rituximab and to investigate covariates influencing its pharmacokinetics.

Breast cancer constitutes a metabolically heterogeneous disorder wherein enzymes associated with lipid metabolism are instrumental in tumor progression, adaptation to the microenvironment, and therapeutic response. Beyond their catalytic roles in fatty acid, cholesterol, and phospholipid metabolism, these enzymes may function as regulatory nodes linking lipid flux to membrane remodeling, lipid peroxide detoxification, autophagy-dependent recycling, epithelial-mesenchymal plasticity, tumor-macrophage crosstalk, epigenetic stabilization, and multidrug resistance (MDR). This review adopts a subtype-aware, node-based framework to analyze lipid metabolic enzymes as context-dependent drivers of malignant phenotypes and treatment resistance. Furthermore, pharmacological strategies targeting lipid metabolic pathways-including fatty acid synthase (FASN) inhibition, ferroptosis induction, blockade of fatty acid oxidation, modulation of cholesterol metabolism, and interference with lipid uptake-are examined. The majority of these strategies are currently at preclinical or early translational stages, encountering significant challenges such as toxicity, metabolic compensation, subtype heterogeneity, and inadequate biomarker-guided patient selection. This review emphasizes lipid-metabolism enzymes as potential therapeutic vulnerabilities and underscores the necessity for mechanistic validation, rational combination therapies, and biomarker-driven metabolic stratification in breast cancer.

Disruptor of telomeric silencing 1-like (DOT1L) is the only identified H3K79 methyltransferase and its dysregulation, mutations, or aberrant activity are closely implicated in the pathogenesis and progression of various diseases. Due to their key roles in leukemogenesis and lung carcinogenesis, DOT1L and its mutations have been studied as attractive therapeutic targets for over a decade, resulting in the identification of numerous DOT1L inhibitors. Herein, we provide an overview of the structural features of DOT1LWT/MUT, as well as their associated signaling pathways and diseases. We summarize recent advances in orthosteric and allosteric DOT1L inhibitors, with their design strategies comprehensively analyzed based on the "Induced-fit" allosteric model. Furthermore, emerging strategies including protein-protein interaction (PPI) inhibitors, proteolysis-targeting chimeras (PROTACs) and combination therapies are also introduced. Finally, we discuss current challenges and future opportunities to provide valuable references for the development of next-generation DOT1L-targeted therapeutics.

While poly ADP-ribose polymerase (PARP) inhibitors represent a promising treatment strategy in early phase trials of patients with high-grade glioma (HGG), the clinical outcomes exhibit variability, mainly due to drug-specific pharmacokinetics and insufficient biological stratification involving MGMT and IDH status. We aimed to investigate the safety and efficacy of PARP inhibitors in grade 3 and 4 gliomas.

Purines and pyrrolo[2,3-d]pyrimidines are privileged heterocyclic scaffolds widely represented in small molecules targeting a broad range of therapeutically relevant targets, including kinases, folate-metabolizing enzymes, histone deacetylases (HDACs), bromodomain containing proteins, membrane transporters, phosphodiesterases (PDEs), ion channels, and toll-like receptors (TLRs). While these scaffolds have been extensively investigated in medicinal chemistry, their role in multitarget drug design has received comparatively less attention. This review provides a comprehensive overview of purine- and pyrrolopyrimidine-based compounds reported over the last two decades from a multitarget medicinal chemistry perspective, with particular emphasis on the design principles and SAR underlying simultaneous modulation of multiple biological targets. By systematically comparing compounds across different target classes, we highlight the key structural features responsible for multitarget activity and discuss how specific scaffold modifications influence potency, selectivity, and polypharmacological profiles. Representative examples are presented to illustrate the successful application of these scaffolds in the development of dual- and multitarget inhibitors with promising anticancer, anti-inflammatory, and drug resistance-overcoming activities. Particular attention is devoted to compounds capable of overcoming drug resistance through the simultaneous modulation of complementary biological pathways. Overall, this review provides an integrated medicinal chemistry framework for understanding multitarget purine- and pyrrolopyrimidine-based ligands and identifies emerging opportunities and challenges for the development of next-generation polypharmacological agents.

The therapeutic landscape of hematologic malignancies has been transformed over the past decade by the shift from conventional chemotherapy to targeted therapies, including proteasome, tyrosine kinase, and epigenetic regulators. Although these agents have significantly improved patient survival outcomes, this progress is tempered by the emergence of distinct cardiovascular toxicities that threaten both patient quality of life and long-term prognosis. Current clinical management is limited by the lack of standardized adverse event reporting mechanisms in trials and the operational complexity of existing risk stratification tools. In this context, a streamlined, personalized surveillance strategy is warranted. Comprehensive baseline cardiovascular assessment is paramount, with the frequency and modality of subsequent monitoring tailored specifically to the agent's mechanism of action and the patient's underlying risk profile. Crucially, when cardiotoxicity arises, the utilization of multidisciplinary cardio-oncology teams is indicated to manage the cardiac condition therapeutically, thereby avoiding the premature discontinuation of life-saving oncologic therapy. The ultimate goal remains maximizing the potent antitumor efficacy of these targeted therapies while rigorously protecting cardiovascular function.

Among several adverse events induced by chemotherapy for patients with far advanced and unresectable cancer, oral mucositis is one that reduces patient quality of life.

Treatment selection beyond second line in metastatic colorectal cancer (mCRC) has evolved from empirical salvage therapy to individualized sequencing. Regorafenib, trifluridine/tipiracil (FTD/TPI), FTD/TPI plus bevacizumab, and fruquintinib have established roles in refractory disease, but their optimal order remains patient-dependent. In parallel, biomarker-guided options for BRAF V600E, KRAS G12C, HER2-positive, MSI-H/dMMR, and rare fusion-positive tumors have expanded the treatment framework. After BREAKWATER, BRAF V600E-mutated mCRC should no longer be viewed only as a later-line subgroup, because eligible patients may already have received first-line encorafenib, cetuximab, and fluoropyrimidine-based chemotherapy. Anti-EGFR rechallenge, preferably guided by circulating tumor DNA, provides another biologically dynamic strategy for selected RAS/BRAF wild-type, left-sided tumors. In Japan, OncoGuide EpiLight has introduced clinically implementable DNA methylation testing, which may complement anti-EGFR sensitivity assessment but does not replace resistance-mutation testing. This review summarizes key evidence and proposes a practical scenario-based framework integrating molecular reassessment, comprehensive genomic profiling, residual toxicity, vascular risk, marrow reserve, frailty, patient preference, and trial access.

The programmed death-1 (PD-1) immune checkpoint is a core regulator of T-cell exhaustion and immune evasion in cancer. While PD-1/PD-L1 monoclonal antibodies have changed the landscape of cancer immunotherapy, there are barriers to broader application due to their large size, potential for systemic toxicities, and high production costs. In this review article, we will focus on therapeutic development, functional applications, and translational advances of anti-PD-1 single-chain variable fragments (scFvs). Advances in phage-display libraries, immunization methods, and antibody engineering have helped develop high-affinity scFvs with novel structural and mechanistic properties. Direct functional applications incorporating anti-PD-1 scFvs are bispecific and trispecific constructs, antibody-drug conjugates (ADCs), immunotoxins, nanoparticles, and biological vector carriers that incorporate checkpoint blockade with targeted cytotoxicity or immunostimulation. Engineered immune cells, such as armored CAR-Ts, NK cells, and MSCs, can secrete or display anti-PD-1 scFvs within the tumor to provide localized checkpoint inhibition, enhance effector-cell persistence, and remodel the tumor microenvironment. Oncolytic and non-replicating viral vectors can further confine scFv activity to tumors, coupling checkpoint blockade with oncolysis, cytokine expression, or bispecific T-cell engagers. Early-phase clinical trials are currently studying TILs and CAR-TILs engineered to secrete scFvs and oncolytic HSV-1 encoding multifunctional checkpoint payloads across a variety of solid tumors. Taken together, anti-PD-1 scFvs represent a modular platform for localized checkpoint inhibition and potentially improved cost-effectiveness compared with systemic antibodies. Future work should prioritize rational combination strategies and well-designed clinical trials that integrate anti-PD-1 scFv platforms with other immunotherapies and standard treatments to maximize clinical benefit.

Cancer continues to cause a major global health challenge, largely because of the heterogeneity of molecular changes that allow cancer cells to grow uncontrollably and evade therapy. The various pathways implicated include HDACs and PI3Ks, which are key epigenetic regulators and intracellular signaling, as well as critical regulators of cell survival and proliferation. Once dysregulated, these pathways contribute to tumor initiation, disease progression, and resistance to currently used treatments. This review presents the biological roles, types, cellular localization, functional diversity, and roles in cancer progression of HDAC and PI3K family members. Further, discussed on the chemistry and SAR of FDA-approved HDAC, PI3K, and dual inhibitors with a special emphasis on the nature of the pharmacophore that affects potency, selectivity, and therapeutic activity. The review focuses on dual HDAC/PI3K inhibition as a single approach to simultaneously inhibit epigenetic regulation and pro-survival signaling in cancer cells. Dual inhibitors, such as CUDC-907 and BEBT-908, and their potential effectiveness in cytogenetic cancers and solid tumors; issues related to clinical trials; and future directions to enhance therapeutic outcomes are discussed. Currently, dual HDAC/PI3K inhibitors are an exciting next-generation anticancer agent that addresses the major drawbacks of existing therapies.

Drug resistance remains a critical clinical bottleneck restricting long-term curative efficacy of chemo-, targeted, and other therapies against human malignancies. Drug-tolerant persister (DTP) cancer cells and intratumoral heterogeneity substantially compromise therapeutic responses and worsen patient clinical prognosis. This review summarizes core epigenetic regulatory mechanisms of drug resistance, including DNA methylation, histone modifications, non-coding RNAs (ncRNAs), N⁶-methyladenosine (m⁶A) RNA methylation, and metabolism-epigenetic crosstalk axis, elaborating the mechanistic links between epigenetic programming and the acquisition of tumor drug resistance. The dynamic epigenetic alterations remodel aberrant transcriptional landscapes to empower cancer cells to circumvent cytotoxic drug elimination. Distinct from irreversible genomic mutations, epigenetic modifications are pharmacologically reversible; such biological plasticity enables combinatorial regimens pairing epigenetic modulators with conventional cytotoxic agents as a viable strategy to reverse therapeutic resistance. In-depth dissection of the epigenetic regulatory networks facilitates identification of novel epigenetic biomarkers and druggable targets, providing rationale for developing personalized combination therapies and ultimately improving clinical outcomes of drug-resistant cancer patients.

Chemoresistance is one of the primary reasons that cancer chemotherapy fails to deliver successful treatment outcomes and contributes to poor overall survival rates for patients with cancer. New research has begun to shed light on the effects of the gut microbiome (GM). This new research will examine how certain microorganisms (referred to as "bad bacteria") can contribute to cancer treatment failure, as well as how others (such as Bifidobacterium, Akkermansia, and Lactobacillus) can enhance treatment success. This review will focus on the molecular mechanisms underlying these effects, including drug metabolism by microorganisms, modulation of the immune system by microorganisms, regulation of cellular apoptosis by microorganisms, and metabolic crosstalk between tumor tissue and the microbiome. Finally, we will look at new therapies under development that leverage knowledge of the microbiome to combat chemoresistance, including fecal microbiota transplantation, targeted probiotic and prebiotic supplementation, and dietary modifications. By studying the complex interactions among the host, the microbiome, and chemotherapeutic agents, we hope to demonstrate how microbiome-centered approaches can tailor and enhance an individual's cancer treatment while transforming the GM from a passive participant to an active target in cancer therapy.

Nano-azurin is redox-active protein has recently attracted attention as potential multifunctional therapeutics, primarily in infectious disease and cancer. This review highlights its potential against Campylobacter spp., including antibiotic resistant variants, in addition to anticancer properties. Campylobacteriosis is a serious public health problem worldwide because of its zoonotic potential and the increasing antimicrobial resistance (AMR) rates as well as its relationship with gastrointestinal carcinogenesis. Nano-azurin not only affects microbial viability and biofilm formation, but also stimulates host immune responses. In cancer settings, it specifically binds to neoplastic cells inducing apoptosis and preventing tumor growth. In particular, a nanoformulation can enhance the stability of the drug, its bioavailability and its selective delivery by lowering systemic toxicity. Moreover, nano-azurin regulates innate immunity functions contributing to the elimination of pathogens and the immune surveillance of tumours. The dual-action profile is promising, though several obstacles with respect to large-scale manufacturing, pharmacokinetics behaviours and clinical translation are important. In summary, nano-azurin is a new nanobiotherapeutic platform at the cross between antimicrobial therapy and cancer immunotherapy, which shows great promise for treatment of malignancies related to infections.

Malignant tumors represent a major threat to human health, underscoring an urgent need for the development of innovative therapeutic strategies. Tumor catalytic therapy has emerged as a promising approach that leverages the acidic tumor microenvironment (TME) and the rational design of pH-responsive catalytic nanomaterials to achieve safe and effective cancer treatment. This review summarizes the acidic characteristics of the TME and the design and synthesis strategies of pH-responsive nanocatalysts. These materials remain inert under normal physiological conditions (pH ≈ 7.4) but are specifically activated within the acidic TME (pH < 6.5), enabling the in situ generation of antitumor agents. Mechanistically, these nanocatalysts catalyze the production of cytotoxic species within the acidic TME, thereby inducing apoptosis or necrosis in tumor cells with high selectivity. This review further discusses the therapeutic potential of these platforms, including their integration with other treatment modalities, strategies to enhance therapeutic efficacy, and current methods for evaluating bio-compatibility and bio-safety. Key challenges are also addressed, such as material stability, tumor heterogeneity, and bio-safety concerns. Finally, future research directions are proposed, emphasizing the need for optimized material design to improve treatment efficiency and minimize side effects. Notably, this review introduces a mechanism-based classification framework and traces the evolutionary trajectory of the field from passive pH-responsive systems to self-amplifying cascades and intelligent feedback-controlled platforms, offering a distinctive perspective that differentiates it from existing literature. In summary, pH-responsive tumor catalytic therapy represents a highly promising paradigm for cancer treatment, and this review serves as a comprehensive reference to guide further progress in this field.

The growing burden of cancer has made it a significant global health concern with increasingly serious implications for public health worldwide. The therapeutic index of conventional anticancer drugs has been severely constrained by their lack of selectivity and undesirable therapeutic consequences. Thus, the development of nanomaterials has brought new hope for improving cancer therapy. Specifically, polymeric nanomaterials have gained considerable attention due to their biocompatibility, improved pharmacokinetics and pharmacodynamics performance, reduced side effects, high retention time, and ability to carry/conjugate diverse therapeutic agents. Also, to overcome the limitations of diffuse distribution and nonspecific intracellular interactions, precise targeting strategies can be introduced in polymeric nanoparticles. In this regard, subcellular organelle-targeting cancer therapy has emerged as a highly precise strategy for selectively eliminating cancer cells. By disrupting organelle function, it enhances therapeutic efficacy, minimizes side effects, overcomes multidrug resistance, and reduces recurrence. Recently, there has been growing interest in polymeric nanomaterials capable of targeting specific cancer cell organelles. This review highlights recent advances (2016-present) in organelle-targeted polymeric nanomaterials for cancer treatment, emphasizing their therapeutic potential, current challenges, and future perspectives to improve clinical translation and treatment efficacy.

FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase (RTK) important for hematopoietic stem cell proliferation, differentiation, and survival. Ligand-induced dimerization activates the downstream pathways such as RAS/MAPK, PI3K/AKT, and STAT5. Mutations such as internal tandem duplications (ITD) and tyrosine kinase domain (TKD) cause constitutive activation, poor prognosis, and driving leukemogenesis in acute myeloid leukemia (AML). Over the past 5 years, FLT3-targeted therapy has advanced significantly. Second-generation FLT3 inhibitors such as gilteritinib and quizartinib displayed improved selectivity and durable efficacy. Quizartinib was approved in 2023 for FLT3-ITD-positive AML alongside intensive chemotherapy. Clinical trials have explored some compounds such as crenolanib, momelotinib, and various novel molecules in combination regimens, which are enhancing remission rates. This review comprehensively compiles diverse chemical scaffolds investigated as FLT3 inhibitors such as pyrimidine, benzimidazole, imidazole, indole, isoxazole, quinazoline, and so on. Structure-activity relationship (SAR) analyses and molecular docking studies are briefly discussed along with highlighting potency against FLT3-ITD and resistant FLT3-TKD mutants. Despite therapeutic gains, resistance through secondary mutations or compensatory pathway activation remains a challenge. Future directions should focus on structure-guided design, rational combination therapies, and expanding applications to other FLT3-altered malignancies. This review integrates updated FLT3 biology, clinical outcomes, medicinal chemistry, and computational insights to support personalized FLT3-targeted treatment strategies.

Thioredoxin reductase (TrxR), a master regulator of intracellular redox homeostasis, is a validated antitumor target. α,β-Unsaturated ketones are potent irreversible TrxR inhibitors with robust in vitro anticancer activity, yet their clinical translation is hindered by critical druggability deficits: poor pharmacokinetics (low solubility, metabolic instability, and low bioavailability) and insufficient tumor selectivity (off-target toxicity and weak tumor tropism). This review systematically summarizes structural optimization strategies to address these limitations. To improve pharmacokinetics, core tactics include introducing polar heterocycles/hydrophilic groups, modifying skeletons, replacing labile moieties, and hybridizing pharmacophores with subcellular targeting motifs. To enhance tumor selectivity, electronic effect modulation, lipophilicity tuning, scaffold rigidification, tumor-targeting moiety conjugation, and electrophilic center regulation reduce off-target effects. Additionally, tumor-specific redox properties are harnessed to boost intratumoral enrichment. The review further highlights current limitations (e.g., overreliance on natural product modifications, lack of universal SAR frameworks, and inadequate ADME regulation) and prospects future directions: structure-based rational design, tumor microenvironment-responsive prodrugs, multi-target synergism, reversible-irreversible switchable inhibitors, and nanodelivery integration. Collectively, these optimizations lay a theoretical foundation for developing safe, effective TrxR inhibitors to advance precision cancer therapy.

Sunitinib malate (SNB) is a multitargeted tyrosine kinase inhibitor that inhibits tumor angiogenesis and proliferation by blocking signaling through VEGFR, PDGFR, c-KIT, FLT3, and RET. SNB is currently used in the treatment of renal cell carcinoma, gastrointestinal stromal tumors, and pancreatic neuroendocrine tumors. The pharmacological efficacy of SNB is limited by its poor aqueous solubility, pH-dependent dissolution, poor oral bioavailability, extensive first pass metabolism, high interpatient pharmacokinetic variability, and dose-limiting toxicities such as cardiotoxicity, hypertension, and myelosuppression. Nanotechnology-based drug delivery systems have been explored as a promising strategy to overcome the limitations and improve the pharmacological efficacy of SNB. A wide variety of SNB-loaded nanocarriers, including polymeric nanoparticles, lipid-based nanocarriers, nanocapsules, polymeric micelles, dendrimers, and inorganic nanostructures, have been developed to improve solubilization, protect the drug from degradation, and provide controlled or stimulus-responsive release. These nanocarriers provide improved pharmacokinetic properties by prolonging systemic circulation, increasing tumor accumulation through enhanced permeability and retention effects, and reducing off-target exposure. Active targeting and intracellular delivery mechanisms further enhance cellular uptake and pharmacological efficacy while reducing systemic toxicity. In addition, multifunctional nanocarriers that incorporate imaging agents or microenvironment-responsive components also offer opportunities for theranostic and precision oncology applications. However, clinical adoption is currently hindered by challenges associated with large-scale nanomanufacturing, batch-to-batch reproducibility, long-term nanostability, regulatory acceptance, and limited human data. This review critically evaluates current nanocarrier platforms for SNB delivery, provides pharmacological advancements achieved through nanoformulation, and identifies key translational hurdles and future directions for clinical adoption.

Autophagy is an essential cellular process that maintains homeostasis, regulates organelle turnover, preserves energy balance, and ensures protein quality control. Central to autophagy regulation is calcium (Ca²⁺) signaling, which integrates inputs from multiple Ca²⁺ channels and handling proteins, including L-type and T-type voltage-gated Ca²⁺ channels, transient receptor potential mucolipin (TRPML) channels, inositol 1,4,5-trisphosphate receptors (IP3Rs), ryanodine receptors (RyRs), the mitochondrial calcium uniporter (MCU), sodium-calcium exchangers (NCX), sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA), and calcium/calmodulin-dependent protein kinase II (CaMKII). Although these regulators are well studied, their disease-specific functions remain context-dependent and complex. In cancer, Ca²⁺-regulated autophagy enhances metabolic flexibility, maintains mitochondrial integrity, promotes resistance to chemotherapy, and facilitates immune evasion, thereby supporting tumor growth and survival. Conversely, in cardiovascular diseases (CVDs), autophagy enables cardiomyocytes to adapt to ischemic, inflammatory, and hemodynamic stress. However, dysregulated Ca²⁺ signaling and impaired autophagic flux contribute to tumor progression and pathological cardiac remodeling, respectively. This review explores the molecular mechanisms underlying Ca²⁺-dependent autophagy in cancer and CVDs, providing a detailed analysis of shared signaling pathways and potential therapeutic targets. Discussed in this review, the emerging field of cardio-oncology highlights a mechanistic convergence in which anticancer therapies disrupt cardiomyocyte Ca²⁺ homeostasis, causing mitochondrial Ca²⁺ overload, ER stress, and defective autophagy, ultimately leading to cardiotoxicity, while tumor cells exploit the same pathways to survive therapeutic stress. By elucidating the spatiotemporal dynamics of Ca²⁺ signaling and autophagy, we identify common molecular hubs and propose precision strategies to enhance anticancer efficacy while preserving cardiac function, advancing translational innovation in cardio-oncology.