Aug 2026· Molecules· Vol 31, pp. 2779· 0 citations· 36 references
Medicine
TL;DR
Findings demonstrate that glucosinolate-derived metabolites from L. latifolium interfere with metabolic and inflammatory pathways critical for KRAS-driven tumor survival and support the therapeutic potential of Brassicaceae-derived epithionitriles as multitarget anticancer agents.
Abstract
Pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) are aggressive malignancies frequently driven by oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations associated with metabolic reprogramming and resistance to apoptosis. In this study, we evaluated the antitumor and anti-inflammatory activity of a Lepidium latifolium L.-derived formulation (CTP) enriched in glucosinolate hydrolysis products in KRAS-mutant colorectal and pancreatic cancer models. The formulation was designed to promote the generation of the epithionitrile 1-cyano-2,3-epithiopropane (CETP) through iron-dependent myrosinase-mediated sinigrin hydrolysis. CTP induced dose-dependent cytotoxicity and morphological alterations consistent with apoptosis in KRAS-mutant cancer cell lines. Treatment significantly reduced mitochondrial membrane potential, ATP production, oxygen consumption rate (OCR), and extracellular acidification rate (ECAR), indicating severe bioenergetic impairment. In parallel, CTP downregulated the metabolic and proliferative regulators C-myc, PKM2, GLUT1, and Cyclin E1. RNA-seq analysis revealed extensive transcriptional reprogramming associated with oxidative stress, metabolic adaptation, and cell-cycle regulation. In addition, CTP significantly suppressed nitric oxide, IL-6, and IL-8 production in LPS-stimulated RAW 264.7 macrophages. These findings demonstrate that glucosinolate-derived metabolites from L. latifolium interfere with metabolic and inflammatory pathways critical for KRAS-driven tumor survival and support the therapeutic potential of Brassicaceae-derived epithionitriles as multitarget anticancer agents.
Background: Drug repurposing represents an accelerated and cost-effective approach to discovering novel oncologic therapeutics. Here, we investigated the anticancer potential and underlying mechanisms of marbofloxacin (MBF), a veterinary fluoroquinolone (FQ), against breast cancer (BC) cells. Methods: The cellular impacts of MBF on cell viability, anchorage-dependent growth, tumorigenicity, migration, apoptosis, proliferation, senescence, and mitochondrial function were thoroughly characterized. To further elucidate its mechanistic activity, real-time qRT-PCR, untargeted LC-MS/MS-based metabolomics, network pharmacology, and molecular docking analysis were integrated. Results: MBF suppressed BC cell growth by inhibiting cellular proliferation and migration, disrupting mitochondrial membrane potential, and inducing ROS-mediated apoptosis and irreversible cellular senescence. These phenotypic impacts were accompanied by upregulation of tumor suppressors such as CDKN1A and PUMA and downregulation of oncogenes including MKI67, BIRC5, and BCL-2. Metabolomic analysis revealed broad suppression of biosynthesis-related metabolic pathways, characterized by the depletion of critical polyamines and nucleotide pathways. Network pharmacology and molecular docking analyses identified EGFR and HSP90AA1 as putative hub proteins potentially associated with the observed anticancer phenotype. Conclusions: These results provide initial evidence that MBF induces metabolic and molecular rewiring in BC, highlighting its promise as a repositionable therapeutic candidate.
M. Yavuz, F. R. P. Dewi, Ilknur Keskin et al.· Pharmaceuticals· 0 citations
HG-AMF and GA converge on G6PD-dependent metabolism and chemoresistance pathways, providing a rational basis for their combined application in PDAC therapy.
Nahyun Park, Changyul Kim, Hee Sung Park et al.· Anticancer Research· 0 citations
OBJECTIVE
Cancer cells frequently exploit the Pentose Phosphate Pathway (PPP) to fuel antioxidant defenses and the synthesis of essential biomolecular precursors. It is hypothesized that sustained upregulation of glucose flux through the PPP is crucial for meeting the anabolic demands of cancer cells and mitigating oxidative stress. We investigated whether pharmacological inhibition of the rate-limiting PPP enzyme, glucose 6-phosphate dehydrogenase (G6PD), could decrease proliferation, disrupt cell-cell interactions, and impede migration in oral squamous cell carcinoma (OSCC).
DESIGN
Non-tumorigenic keratinocytes (HaCaT), less invasive (CAL27) and highly invasive (SCC9) OSCC had the G6PD pathway inhibited using 6-aminonicotinamide (6-AN) and then submitted to proliferation, spheroid formation, and cell migration assays.
RESULTS
Inhibition of G6PD significantly decreased cell proliferation, disrupted spheroid integrity, and reduced migratory capacity across both OSCC cell lines, while exhibiting only moderate cytotoxicity towards non-tumorigenic keratinocytes, yielding Selectivity Index (SI) values of 1.47 for CAL27 and 3.39 for highly invasive SCC9 cells.
CONCLUSION
Given that cancer cells often detach and migrate within challenging microenvironments, the ability of 6-AN to induce metabolic stress and impede both cell-cell interactions and migration highlights its potential as an adjuvant therapeutic strategy against OSCC progression.
L. Diel, S. E. C. de Mattos, Julia Stela Xavier Paim et al.· Archives of Oral Biology· 0 citations
Breast cancer cells exhibit a reversed pH gradient and metabolic plasticity that promote proliferation, invasion, and resistance to therapy. Natural products such as chlorogenic acid (CGA) and cinnamaldehyde (CA) have shown emerging anticancer potential. However, their effects on intracellular pH and metabolic transport systems remain undefined. Therefore, the aim of this study was to characterize these parameters in breast cancer and non-tumorigenic breast cells. This study evaluated the physiochemical properties of CGA and CA using LC–MS, under pH conditions (pH 1.2, 7.4, and 9.0) mimicking the gastrointestinal track (GIT). Additionally, LC–MS-based human liver microsome (HLM) assays with NADPH were used to evaluate susceptibility to CYP-mediated metabolism to evaluate first-pass metabolic stability. Intracellular uptake kinetics were quantified at multiple time points using LC–MS. Following CGA:CA treatment, intracellular pH (pHi) was measured in cancerous MDA-MB-231 and non-tumorigenic MCF-10A breast cell lines using SNARF-1 targeted ratio-metric fluorescence approach. Expression of OATP1B1, GLUT1, and MCT1 were analyzed by Western and immunofluorescence respectively, to assess potential cellular uptake of CGA:CA through OATP1B1 and their effects on glucose uptake and lactate and proton transport. Physiochemical results demonstrated that the compounds ranged from fully stable (pH 1.2 and 7.4) to completely unstable (pH 9.0). HLM incubation indicated no CYP-mediated hepatic metabolism. Treatment results showed that there was rapid intracellular uptake of CGA and CA in cancer cells and that CGA:CA lowered pHi in both MDA-MB-231 and MCF-7 cells, while pHi remained mostly unchanged in MCF-10A cells. Protein analysis revealed that CGA:CA treatment downregulated GLUT1 and MCT1 expression in cancer cells, suggesting impaired glycolytic activity and lactate shuttling. OATP1B1 expression was significantly suppressed in cancer cells, suggesting feedback inhibition of the solute carrier protein. Collectively, these findings indicate that CGA and CA exhibit favorable biochemical stability and disrupt intracellular pH regulation and metabolic transporter expression in breast cancer cells. Importantly, normal cells are not significantly affected. Thus, CGA:CA demonstrates therapeutic potential for breast cancer through pHi and metabolic modulation.
Yusuff Olayiwola, Vindya Edgunpati, Li Li et al.· Molecules· 0 citations
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies worldwide due to its aggressive nature and limited therapeutic options. HMTA (4-hydroxy-2-methoxy-6-tridecylphenyl acetate), a natural alkylphenol derived from Ardisia virens Kurz, has previously demonstrated anti-tumor potential as a tubulin polymerization inhibitor. However, its impact on the autophagic machinery in pancreatic cancer remains to be elucidated. In this study, we investigated the anti-cancer effects of HMTA across four human pancreatic cancer cell lines (PANC-1, BxPC-3, MIA PaCa-2, and AsPC-1) with varying KRAS mutation statuses. HMTA significantly inhibited cell viability in a dose-dependent manner. Mechanistically, HMTA treatment led to a substantial accumulation of LC3-II and p62/SQSTM1 proteins. Notably, the expression of upstream autophagy-initiating markers, such as ATG5 and Beclin-1, remained unchanged, suggesting a defect in autophagic clearance rather than induction. Using a tandem mRFP-EGFP-LC3 fluorescence reporter assay, we found that HMTA obstructs autophagic flux by preventing the fusion of autophagosomes with lysosomes. Furthermore, the combination of HMTA with the autophagy inhibitor chloroquine resulted in enhanced cytotoxicity, whereas the early-stage inhibitor 3-MA partially rescued HMTA-induced cell death. Our findings demonstrate that HMTA exerts its anti-pancreatic cancer activity mainly through the blockade of autophagic flux, regardless of KRAS background. These results position HMTA as a promising therapeutic candidate for the treatment of PDAC.
Yu-Fang Chuang, Ying-Ray Lee, Wan-Chin Tsai· American Journal of Cancer R...· 0 citations
OBJECTIVE
This study aims to elucidate the molecular mechanisms by which Polyphyllin I (PPI), a potent steroidal saponin, attenuates non-small cell lung cancer (NSCLC) progression via mechanistic reprogramming of an autophagy-dependent immunogenic response.
METHODS
Integrated in vitro (A549, H460) and in vivo (LLC xenograft) models were deployed to evaluate PPI's efficacy on autophagic flux and the tumour immune microenvironment. The regulatory role of autophagy in macrophage-mediated antigen presentation was scrutinised via ATG3-mediated genetic silencing or overexpression in tumour-macrophage co-culture systems. Concurrently, the capacity of PPI to sensitise NSCLC cells to cisplatin (DDP) and counteract chemoresistance was evaluated.
RESULTS
PPI activated the AMPK/p53/mTOR signalling axis, robustly inducing core autophagic markers (LC3-II and Beclin-1) in a dose-dependent manner. Mechanistically, PPI-induced autophagic flux served as a prerequisite for antitumoural M1 macrophage polarisation, characterised by significant upregulation of iNOS and MHC-II in co-cultured THP-1 cells. Genetic knockdown of ATG3 effectively abrogated these immunostimulatory profiles, whereas ATG3 overexpression potentiated PPI-driven antigen presentation. Furthermore, PPI administration markedly delayed the onset of DDP resistance sustained by functional autophagic flux. In vivo, PPI significantly suppressed tumour burden, accompanied by enhanced CD8+ T-cell infiltration and elevated cytotoxic effector levels (IFN-γ and Granzyme B).
CONCLUSION
Our findings establish PPI as a dual autophagic-immune modulator that re-engineers the immunosuppressive microenvironment. By coupling intracellular autophagic stress with macrophage-mediated antigen presentation, PPI reinstates antitumour immunity and abrogates chemoresistance, offering a compelling therapeutic framework for managing recalcitrant NSCLC.
Zongxu Liu, Yanping Li, Shumin Li et al.· Clinical and Experimental Ph...· 0 citations
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