Resistance to single-target therapies has spurred interest in multitarget strategies for acute myeloid leukemia (AML). Heat shock protein 90 (HSP90), a chaperone that stabilizes numerous oncogenic client proteins, represents an attractive therapeutic target for AML; however, the clinical development of early HSP90 inhibitors was limited by dose-limiting toxicities and an excessive heat-shock response (HSR). Through structural optimization of the marine aaptamine scaffold and target identification, ap-a48 was identified as a novel HSP90-targeting anti-AML lead that exhibits potent anti-AML activity and acceptable preliminary tolerability while inducing only a modest HSR. In rats, ap-a48 showed favorable pharmacokinetics with 65.3% oral bioavailability, and in HL-60 xenograft mouse models, it suppressed tumor growth (71.2% inhibition at intraperitoneal 40 mg/kg; 67.3% at oral 60 mg/kg) without significant hepatotoxicity or major organ abnormalities. These findings identify ap-a48 as a promising marine-natural-product-derived HSP90-targeting lead for AML therapy.

Hematopoietic progenitor kinase 1 (HPK1) functions as an intracellular negative regulator of T-cell receptor signaling, and its inhibition has emerged as a promising strategy to counteract T-cell exhaustion and potentiate antitumor immunity. Through rational structural optimization of a recently reported HPK1 inhibitor 12 bearing a monocyclic thiazole skeleton, we developed a new inhibitor 23 featuring a bicyclic thiazolo[5,4-c]pyridine component. This new inhibitor exhibits potent HPK1 inhibition, high selectivity within the MAP4K family, along with improved metabolic properties and reduced hERG liability. Mechanistically, compound 23 effectively suppressed HPK1 activation in cells and restored TCR signaling, resulting in a marked enhancement of T-cell function in both naïve and antigen-specific responses. In xenograft tumor models, compound 23 demonstrated robust monotherapy efficacy and synergizes with an anti-PD-1 antibody or an anti-PD-L1/IL-15 immunocytokine prodrug. The balanced potency, good safety and optimized pharmacokinetics warrant compound 23 for further preclinical evaluation.

Novel bacterial topoisomerase inhibitors (NBTIs) target bacterial topoisomerases through binding modes distinct from fluoroquinolones but are often limited by hERG channel inhibition. Our previous findings indicated that the introduction of a non-aminopiperidine linker and a halogenated phenyl enzyme-binding moiety can partially reduce cardiotoxicity. In this paper, we describe whether optimizing the DNA-intercalating 1,5-naphthyridine moiety could further improve safety while maintaining antibacterial potency. Several optimized compounds showed strong enzyme inhibition and potent antibacterial activity, particularly against Gram-positive pathogens. Compound 13 displayed broad-spectrum activity, with MICs as low as 0.008 μg/mL against Gram-positive and 0.125 μg/mL against Gram-negative bacteria. Safety profiling revealed reduced cytotoxicity and hERG binding compared to earlier series. Compounds 6, 20, 24, and 25 were nontoxic in zebrafish embryo assays. Compound 13 showed toxicity only at high doses and protected embryos in a lethalStaphylococcus aureus infection model, highlighting its potential as a preclinical lead.

The development of cyclin-dependent kinase 7 (CDK7) inhibitors represents a promising therapeutic strategy for triple-negative breast cancer (TNBC). Herein, we designed and synthesized 21 novel CDK7-targeted small molecules and identified ZJC-11 as a potent lead candidate. ZJC-11 demonstrated significant antiproliferative activity against TNBC both in vitro and in vivo, with reduced toxicity compared to the reported CDK7 inhibitor THZ1. Molecular docking, Kinact/KI tests, kinase selectivity profiling, and pharmacokinetic studies confirmed that ZJC-11 selectively and covalently targets CDK7 with favorable pharmacokinetic properties. RNA sequencing and functional analyses revealed that ZJC-11 not only suppresses transcription and G2/M cell cycle checkpoint pathways but also induces DNA damage-driven cellular senescence, ultimately leading to TNBC cell death. Moreover, ZJC-11 not only exhibited a synergistic anti-TNBC effect when combined with doxorubicin but also alleviated doxorubicin-induced cardiotoxicity, a clinically significant adverse effect, highlighting its promise as a therapeutic candidate for TNBC treatment.

Altered platinum chemotherapy sensitivity is a major determinant of treatment outcome in ovarian cancer; however, the molecular mechanisms underlying adaptive chemotherapy responses remain incompletely understood. Sphingomyelin synthase 1 (SMS1) and sphingomyelin synthase 2 (SMS2), key enzymes involved in sphingomyelin biosynthesis, have been implicated in cancer biology, but their roles in platinum chemotherapy response remain unclear.

This scoping review aimed to map the existing evidence on the associations between habitual food group intake and chemotherapy-induced toxicity and to identify critical gaps in the literature.

Microtubules assembled from α/β-tubulin heterodimers are critical for cell division and well-established anticancer drug targets, making tubulin polymerization inhibitors a viable route for new chemotherapeutics. Guided by structural analysis of colchicine-site binders and tubulin-ligand computational simulations, we rationally designed and synthesized a series of 6-aryl-1-(3,4,5-trimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidines as novel colchicine-binding site tubulin inhibitors. Derivative 9t displayed the strongest antiproliferative potency, with IC₅。 values of 0.065-0.096 μM across tested cancer lines. It exerted minimal toxicity to normal L929 fibroblasts, yielding a selectivity index over 300. Mechanistic assays confirmed 9t suppresses cell-free tubulin polymerization, destroys cellular microtubule architecture, induces persistent G₂/M cell cycle arrest, and activates cancer cell apoptosis. Overall, 9t serves as a promising dual-function tubulin inhibitor with both cytostatic and cytotoxic anticancer effects, meriting further preclinical investigation.

The role of microbes in cancer is gaining attention these days, especially in the context of tumor-associated biofilms and dysbiotic microbiota. Biofilm-producing microorganisms, such as Fusobacterium nucleatum and Helicobacter pylori, trigger oncogenic inflammation and immune evasion in tumor initiation and progression, and in the development of chemoresistance, through the activation of the NF-κB, STAT3, and β-catenin pathways. Dietary terpenoids are a structurally diverse group of antitumor and antibiofilm plant metabolites. Monoterpenoids, sesquiterpenoids, and triterpenoids are known to inhibit quorum sensing, the biosynthesis of extracellular polymeric substances (EPS), and the expression of biofilm-associated virulence factors, proposing an unexplored convergence among antibiofilm and anticancer mechanisms. Importantly, the biofilm structure (thickness, developmental stage, EPS density) affects the efficacy of terpenoids, affecting diffusion, microbial persistence, and therapeutic susceptibility. The quorum-sensing disruption is more effective in the early stages of biofilms, while high concentrations of EPS in mature, thick biofilms will require more penetration to disrupt quorum sensing. Innovative functional food matrices, including nano-enabled delivery systems, are emerging strategies to improve bioavailability and microbiome modulation of terpenoids. Furthermore, nano-formulations allow better penetration in dense biofilm matrices, protect terpenoids from early degradation, and allow prolonged and focused drug release in the tumor microenvironment associated with biofilms. Combining precision nutrition with microbiome-informed dietary strategies can be used to prevent and treat cancer. The present review combines studies linking biofilm-driven carcinogenesis with terpenoid-mediated antibiofilm-anticancer pathways and nano-mediated functional delivery and biofilm penetration, including highlighting the potential for microbiome modulation in cancer therapy.

Angiogenesis, regulated by vascular endothelial growth factor (VEGF), is crucial in tumor growth, metastasis, and inflammation. Leonurus japonicus Houtt., a traditional Chinese herb, was investigated for its anti-angiogenic potential. DNA sequencing confirmed its identity, distinguishing it from the common morphological misidentification with Leonurus sibiricus by the public. Using UHPLC-MS/MS and GNPS (Global Natural Products Social) molecular networking on the active methanol partition, over 6000 nodes were grouped into 273 clusters. Diterpenoids and flavonoids were targeted. Six compounds were successfully isolated from L. japonicus, including four labdane-type diterpenoids (1-4) and two flavonoids (5, 6) using column chromatography. Compound 1, (-)-8S-acetoxy-15,16-epoxy-8,9-seco-13(16),14-labdadiene, was a new stereoisomer, while Compound 6, nevadensin, was reported for the first time from this species. Compounds were characterized by NMR, ESI-MS, and ECD. At 50 μM, Compounds 1, 4, and 5 exhibited inhibitory effects in endothelial progenitor cell (EPC) tube formation. Molecular docking and dynamics simulations supported this anti-angiogenic activity. Compound 1 showed the highest VEGFR-2 binding affinity (-9.24 kcal/mol), comparable to sunitinib (-9.52 kcal/mol), further verified by an immunoblotting assay. This study demonstrated the successful integration of GNPS and bioactivity-guided isolation for identifying natural VEGFR-2 inhibitors. Our findings highlight Compounds 1 and 4 as promising lead candidates for anti-angiogenic therapy.

Immune checkpoint inhibitor (ICI)-related overlap syndrome involving myositis, myocarditis, and myasthenia gravis (3M overlap syndrome) is rare but potentially fatal. Current evidence is derived mainly from case reports and small case series, and individual case-level data on ancillary diagnostic findings, baseline comorbidities, treatment patterns, and short-term outcomes remain limited.

Breast cancer is the most common malignancy in females internationally. Doxorubicin (DOX) has been well-thought-out as the most effective regimen for breast cancer treatment for several years. The chronic side effects of DOX obligate us to control the dosage that can be used, although its efficacy. Radiotherapy is a vigorous regimen in breast cancer treatment, but correlated side effects are determining factors for a successful recovery. Combined metronomic chemotherapy and radiotherapy, at low doses, can reduce the side effects of single-modality treatments. We have studied the dose 1.8 mg/kg twice per week for 8 weeks of DOX singly or with 0.5 Gy fractionated doses of gamma radiation on inducing cell death, cell cycle arrest, and apoptosis, and also P53, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X (Bax), and caspase-3 gene expression in an animal breast cancer model. Treatment with DOX resulted in upregulation of apoptosis and downregulation of cell division at an accumulated dose of 0.5 Gy, as well as downregulation of Bcl-2 gene expression and upregulation of p53, Bax, and caspase-3 gene expression in animals bearing breast cancer. In addition, DOX in combination with radiation decreased the tumor size. A metronomic dose of DOX, when used with a low dose of gamma radiation, with the least side effects, could be a successful treatment for breast cancer in clinical trials.

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) have transformed precision oncology by exploiting synthetic lethality in homologous recombination (HR)-deficient cancers, with multiple FDA-approved agents targeting BRCA1/2-mutant tumors. Despite initial efficacy, resistance inevitably emerges, limiting long-term clinical benefit. This review synthesizes emerging mechanistic insights into PARPi response and resistance. Recent evidence reframes PARP inhibition cytotoxicity through a transcription-replication conflict model and identifies single-stranded DNA gaps as the primary lethal lesion in HR-deficient cells, rather than double-strand breaks. These findings suggest that resistance reflects restoration of replication gap suppression or resolution of transcription-replication stress. We further highlight DNA ligase III as a collateral vulnerability in 53BP1-deficient resistant tumors, and discuss proteolysis-targeting chimera (PROTAC)-based PARP1 degraders as a strategy to overcome resistance and induce alternative cell death pathways. Established resistance mechanisms-including BRCA1/2 reversion mutations, shieldin complex loss, RAD51 hyperactivation, and pharmacokinetic alterations-are reconsidered within this updated framework. Combination strategies with ATR inhibitors show promising clinical activity in PARPi-resistant HR-deficient ovarian cancer. Finally, we propose an integrated biomarker framework combining HRD scar assays, functional RAD51 foci analysis, replication gap profiling, and circulating tumor DNA (ctDNA) monitoring to enable dynamic resistance tracking.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide. Approximately 15% of localized and 5% of metastatic cases exhibit mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H). While immune checkpoint inhibitors (ICIs) have revolutionized the first-line treatment for this subgroup, 15%-46% of patients experience primary resistance, and a subset of responders eventually acquires resistance. This review synthesizes the multifaceted mechanisms underlying ICI resistance in dMMR/MSI-H CRC. We delineate tumor-intrinsic alterations, including defects in the antigen presentation machinery (specifically transporter associated with antigen processing [TAP]1/TAP2 and β2-microglobulin [β2m]), oncogenic signaling via the Wnt/β-catenin and JAK/STAT pathways, and epigenetic remodeling involving ARID1A. Furthermore, we explore the role of the immunosuppressive tumor microenvironment (TME), characterized by T-cell exclusion and myeloid-derived suppressor cell (MDSC) accumulation. To address these barriers, we evaluate the clinical potential of third-generation ICIs targeting lymphocyte activation gene 3 (LAG-3), T-cell immunoglobulin and mucin-domain-containing-3 (TIM-3), and TIGIT, as well as emerging biomarker strategies such as gut microbiome modulation and circulating tumor DNA (ctDNA) dynamics. By integrating these mechanistic insights with novel therapeutic approaches, including bispecific antibodies (BsAbs) and adoptive cell transfer, this review aims to provide a roadmap for overcoming resistance and advancing precision immunotherapy in dMMR/MSI-H CRC.

Four sesquiterpenes, namely tomentosin, 11α,13-dihydrotomentosin, inuviscolide, and α-costic acid, were isolated from the aerial parts of the medicinal plant Dittrichia viscosa (L.) Greuter and evaluated for antiproliferative activity against HCT116 colorectal and A549 lung cancer cells. All compounds reduced cell viability in a concentration-dependent manner, with tomentosin and inuviscolide exhibiting the greatest activity among the tested compounds and IC50 values in the moderate micromolar range. Evaluation in non-malignant human neonatal dermal fibroblasts (HDFn) revealed compound- and cancer-type-dependent selectivity, with inuviscolide showing greater selectivity toward HCT116 cells and tomentosin showing moderate selectivity toward both cancer cell lines. In silico ADMET and DFT analyses characterized the predicted drug-likeness, pharmacokinetic, toxicity-related, and electronic properties of the compounds, particularly tomentosin and inuviscolide. Network pharmacology prioritized STAT3, ESR1, and PTGS2 as candidate hub targets associated with both cancer types, while enrichment analyses identified pathways related to tumor proliferation, inflammation, immune regulation, and cellular stress. Noncovalent molecular docking, 200 ns molecular dynamics simulations, and MM/GBSA calculations supported possible modeled interactions of tomentosin and inuviscolide with these proteins, with tomentosin displaying the most favorable predicted binding profile. Covalent docking further identified structurally feasible STAT3 CYS687-linked poses with the two sesquiterpenes, although covalent adduct formation and direct target engagement remain to be experimentally validated. Overall, the integrated findings prioritize tomentosin and inuviscolide as D. viscosa-derived natural-product scaffolds with moderate antiproliferative activity for further structural optimization, selectivity assessment, and experimental mechanistic validation.

Phosphatidylinositol 5-phosphate 4-kinase type 2 alpha (PIP4K2A) is a key oncogenic driver that regulates the PI5P/PIP2 axis to promote metastatic migration in breast cancer. This study aimed to investigate the therapeutic potential of a crude extract from Tamarix aphylla against breast cancer progression and identify its primary active constituents. The crude extract was initially evaluated against MDA-MB-231 and MCF7 breast cancer cell lines using wound healing assays. Bioassay-guided isolation and screening were deployed to isolate individual components, and the most potent lead compound was structurally characterized using preparative HPLC and FTIR. To analyze its interaction with PIP4K2A, in silico molecular docking, MM/GBSA calculations, and 200 ns molecular dynamics simulations were conducted. In vitro validation was subsequently performed via dose-dependent cytotoxicity assays, scratch assays, single-cell tracking, and RT-qPCR expression analysis. Quercetin was identified as the most potent lead inhibitor against PIP4K2A. Computational modeling revealed that quercetin binds tightly within the PIP4K2A ATP-binding pocket, yielding a superior binding affinity of -10.77 kcal/mol and enhanced thermodynamic stability (ΔGMM/GBSA = -42.6 ± 2.1 kcal/mol) compared to the native ligand (ΔG MM/GBSA = -23.3 ± 1.8 kcal/mol). Molecular dynamics simulations confirmed an induced-fit structural transition that locked the complex into an ultra-stable conformation within a deep global energy minimum basin (-10.8 kcal/mol). In vitro assays demonstrated dose-dependent cytotoxicity, with aggressive triple-negative MDA-MB-231 cells exhibiting higher sensitivity (IC50 = 82.23 µg/mL) than luminal MCF7 cells (IC50 = 97.14 µg/mL). Furthermore, scratch and single-cell tracking assays showed a profound suppression of migration speed and wound closure (reduced to ~40%), while RT-qPCR revealed a near-complete transcriptional knockdown of PIP4K2A mRNA expression (down to 0.025-fold). Collectively, these findings elucidate a unique dual-action mechanism for Tamarix aphylla-derived quercetin-characterized by both direct competitive enzymatic inhibition and downstream transcriptional silencing-positioning it as a promising therapeutic scaffold for targeted anti-metastatic breast cancer interventions.

Ovarian cancer is among the most lethal gynecological malignancies due to its poor prognosis and lack of early symptoms. Cisplatin remains the primary chemotherapeutic agent; however, resistance to cisplatin in advanced ovarian cancer is a major cause of treatment failure. Pyruvate kinase M2 (PKM2) is markedly upregulated in ovarian cancer tissues and contributes to cisplatin resistance, though its therapeutic relevance has not been fully defined. This study investigated whether shikonin and compound 3K, both PKM2 inhibitors, could enhance anticancer effects in cisplatin-resistant SKOV-3 cells by modulating autophagic pathways. Cytotoxicity assays revealed that treatment with shikonin or compound 3K significantly reduced PKM2 expression. Combination therapy with high-dose PKM2 inhibitors and cisplatin increased apoptosis compared to controls, although the modest induction suggests apoptosis is only partially responsible for the observed effects. Additionally, Shikonin and compound 3K treatment suppressed PKM2-mediated glycolysis and induced autophagic cell death in cisplatin-resistant ovarian cancer cells, as evidenced by increased LC3-II expression, autophagosome formation, and reduced cell viability. These findings indicate that PKM2 overexpression plays a central role in cisplatin resistance in ovarian cancer. Targeting PKM2 with inhibitors such as shikonin or compound 3K may represent a promising strategy to overcome chemoresistance and improve therapeutic outcomes in patients with advanced ovarian cancer. These findings strongly suggest that PKM2 overexpression plays a key role in cisplatin resistance in ovarian cancer. Thus, PKM2 inhibitors use may be a highly effective strategy for overcoming chemoresistance and improving outcomes in patients with advanced ovarian cancer.

This work reports the synthesis, characterization and in vitro evaluation of three organometallic triorganotin(IV) complexes bearing a dicarbamido-bis-organosilane benzoate ligand as potential anticancer agents against colorectal cancer cells. The complexes, Sn(IV)-biSi-1, Sn(IV)-biSi-2 and Sn(IV)-biSi-3, differ in the alkyl groups directly bound to the Sn(IV) center (methyl, n-propyl and isopropyl, respectively). Their structures were confirmed by 1H, 13C and 119Sn NMR spectroscopy, FTIR and ESI-MS, supporting monodentate carboxylate coordination and a solvent-dependent Sn(IV) coordination environment. Biological assays in HCT116 cells showed that the final bis-organosilane complexes were markedly more active than their aminobenzoate intermediates and, under several conditions, more effective than cisplatin. Sn(IV)-biSi-2 and Sn(IV)-biSi-3 reduced cell viability to approximately 30% at 0.5 μM after 5 days and to about 11% and 7%, respectively, at 12.5 μM. In repeated-treatment assays, these complexes maintained antiproliferative activity more efficiently than cisplatin, limiting resistance-like cell recovery. Western blot analysis revealed increased γ-H2AX, p53, cleaved caspase-3 and cleaved PARP, indicating DNA damage-associated apoptotic signaling. Overall, these results identify bis-organosilane triorganotin(IV) benzoates, especially Sn(IV)-biSi-2 and Sn(IV)-biSi-3, as promising metal-based anticancer candidates that sustain antiproliferative activity after repeated exposure in colorectal cancer cells and may contribute to strategies aimed at therapy-resistant colorectal tumors.

Cisplatin is an effective platinum-based chemotherapeutic agent used to treat a variety of cancers. However, its clinical utility is limited by dose-dependent neurotoxicity, yet no approved neuroprotective strategy currently exists. Our integrated cellular, metabolic, and in vivo approaches unraveled the neuroprotective potential of Areca catechu ethyl acetate extract (AC-EA) against cisplatin-induced neurotoxicity. Importantly, AC-EA did not reduce cisplatin-induced cytotoxicity in A549 lung cancer cells. In HT22 hippocampal neurons, AC-EA restored cell viability, suppressed reactive oxygen species generation, preserved mitochondrial-associated fluorescence, and attenuated phosphorylated histone H2AX (γH2AX)-marked DNA damage. AC-EA was associated with increased pNRF2 expression, consistent with activation of NRF2-dependent antioxidant signaling, suppressed inducible nitric oxide synthase iNOS (inducible nitric oxide synthase )-mediated neuroinflammation, and prevented the depletion of total AKT (protein kinase B) protein. Untargeted metabolomics and Caenorhabditis elegans survival assays were performed for mechanistic and in vivo validation. Metabolomics data showed restoration of several critical amino acids, including L-tyrosine and β-alanine, disrupted by cisplatin. Moreover, C. elegans studies confirmed in vivo activation of antioxidants via the SKN-1/GST-4 (glutathione S-transferase 4) pathway. While AC-EA shows neuroprotective potential, arecoline's toxicity demands caution. To our knowledge, this is the first study to demonstrate the neuroprotective activity of A. catechu against cisplatin-induced neurotoxicity, laying the foundation for developing plant-derived adjunct therapies for chemotherapy-associated neuropathy.

RNA-binding proteins (RBPs) remain underexplored as small-molecule targets, although their dysregulation contributes to numerous human diseases, including cancer. RBPs are key regulators of post-transcriptional gene expression, controlling multiple stages of RNA metabolism. Among them, insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is an oncofetal RBP that is highly expressed during embryonic development, largely absent in adult tissues, and re-expressed in multiple malignancies. A growing body of evidence supports IGF2BP3 as a diagnostic and prognostic biomarker and a potent oncogenic driver across tumor types, underscoring its potential as a therapeutic target. However, the development of effective IGF2BP3-targeting compounds remains in its early stages. In this review, we first describe the structural organization of IGF2BP3, the molecular basis of RNA recognition, and the mechanisms underlying its dysregulation across human cancers. We then discuss emerging therapeutic approaches, including direct inhibition of IGF2BP3-RNA interactions and indirect strategies that rewire IGF2BP3 expression or activity through epigenetic, epitranscriptomic, and signaling pathways. By critically highlighting the opportunities and limitations of these approaches and their impact on cancer progression, we provide an integrated perspective combining structural biology, medicinal chemistry, and cancer biology to support the development of next-generation IGF2BP3-targeted therapies.

Oxidative stress in the tumor microenvironment, which is its own intrinsic property, is frequently utilized to deal with the drug-targeting issue in the nanoparticle drug delivery system. For this purpose, reactive oxygen species (ROS)-sensitive nanoparticles encapsulating doxorubicin (DOX) and chlorin e6 (Ce6) were synthesized for treatment of MDA-MB-231 breast cancer cells. Hyaluronic acid (HA) with a reductive end was conjugated with methoxy poly(ethylene glycol) (PEG) using thioketal diamine (ThdNH2) linkage (HA-b-PEG copolymer). Then, Ce6 were conjugated to the carboxylic acid group of HA via ThdNH2 (HA(Ce6)-b-PEG copolymer). DOX was physically incorporated to make DOX-incorporated HA(Ce6)-b-PEG copolymer nanoparticles (DOX-NP). HA(Ce6)-b-PEG copolymer nanoparticles (empty NP) and DOX-NP have a tiny particle size, less than 200 nm, with spherical morphology. They were responsively disintegrated according to the hydrogen peroxide (H2O2) concentration, then the release rate of Ce6 or DOX was accelerated, indicating that empty NP and DOX-NP have ROS sensitivity. DOX-resistant MDA-MB-231 cells were prepared by continuous treatment of DOX for three months. DOX-NP were efficiently internalized into the cells while intra-cellular delivery of DOX itself was inhibited. DOX-NP has higher anticancer activity against DOX-resistant MDA-MB-231 cells than that of DOX itself since cells were resistant to DOX itself. Under light irradiation, DOX-NP significantly decreased the viability of DOX-resistant MDA-MB-231 cells while DOX itself did not properly affect cell viability. Empty NP also efficiently inhibited cell viability rather than that of Ce6 itself while both of them did not affect the cell viability in the absence of light irradiation. Furthermore, empty NP showed higher ROS generation than that of Ce6 itself. DOX-NP more efficiently induced apoptosis/necrosis than DOX itself. In DOX-resistant MDA-MB-231 cell-bearing mice, DOX-NP was efficiently delivered to tumor tissue. DOX-NP greatly inhibited the growth of tumors under light irradiation, more than that of DOX itself or empty NP. In conclusion, DOX-NP showed promising antitumor activity against DOX-resistant MDA-MB-231 cells.