AIM:This study aimed to investigate the role of the tumor microenvironment in two key aspects of cancer progression: regulation of tumor cell motility and development of resistance to targeted therapy. METHODS:In vitro lung adenocarcinoma cell lines were used to assess the effects of hypoxia on cell migration, proliferation, signaling pathway activity, and expression of epithelial- mesenchymal transition (EMT) markers. RESULTS:Hypoxia reduced single-cell motility and proliferation while promoting collective invasion and inducing cell line-specific EMT-related changes. Hypoxia-mimicking CoCl2 treatment failed to reproduce the effects of true hypoxic conditions. In the second part of the study, a patient- derived tumor xenograft (PDTX) model of BRAF V600E mutant melanoma was established to investigate acquired resistance to vemurafenib. Bulk RNA sequencing identified potential resistance-associated markers, however, protein- level validation was inconclusive. CONCLUSIONS:Our results highlight that both hypoxia and therapeutic pressure modulate tumor progression in a complex, context-dependent manner.
Cancer drug resistance remains one of the greatest barriers to durable therapeutic success. Here, we reframe resistance as a dynamic landscape shaped by transporter‑mediated efflux, reversible drug‑tolerant persister states, and therapy‑induced senescence. This review highlights areas where our group has made substantial contributions, with a particular focus on our own experimental and conceptual advances. We show how P‑glycoprotein (P-gp) overexpression, traditionally viewed as an obstacle sustaining cancer multidrug resistance (MDR), creates exploitable metabolic vulnerabilities, enabling the development of MDR‑selective compounds. We demonstrate that persister cells rely on transient P‑gp-mediated detoxification, revealing a therapeutic window during drug‑free intervals. We further show that senescence is not a terminal fate but a relapse‑initiating state requiring targeted intervention. Finally, we illustrate how pharmacokinetics and dosing schedules can be harnessed to reshape tumor evolution, culminating in LiPyDau, a next‑generation liposomal anthracycline with durable activity against resistant tumors. Together, these insights outline a unified strategy for anticipating, intercepting, and ultimately overcoming cancer drug resistance.
Targeting the cytosolic selenoprotein thioredoxin reductase 1 (TrxR1, also named TXNRD1) has emerged as a promising strategy to exploit redox vulnerabilities in cancer. However, both preclinical observations and recent mechanistic studies indicate that TrxR1 inhibition can have context‑dependent outcomes. This article synthesizes a mechanistic framework linking cytosolic redox buffering, proteostasis, receptor tyrosine kinase (RTK) signaling, and immune surveillance with treatment responses. It highlights the dual functional roles of the TrxR1-substrate TXNL1 (also named TRP32), discusses intracellular transcriptional crosstalk shaping treatment sensitivity, and outlines potential combination strategies with RTK modulators.
AIM:Tumor hypoxia is a major driver of tumor progression and metastasis. Hypoxic adaptation is regulated by hypoxiainducible factor-1 (HIF-1), which controls the transcription of genes promoting malignant behavior. HIF-1 inhibitors have failed as monotherapies in clinical trials, highlighting the need for combination-based strategies. This study aimed to develop hypoxia-targeted combination therapies for breast and ovarian cancers. METHODS:Using established in vitro and in vivo hypoxia models, we evaluated acriflavine, a HIF-1 inhibitor, in combination with paclitaxel and an epithelial-mesenchymal transition targeting agent. RESULTS:Acriflavine exerted potent antiproliferative effects, particularly in triple-negative breast cancer cell lines, and proteomic profiling indicated modulation of migration, proliferation, and cellular metabolism. The acriflavine-paclitaxel combination showed synergistic antitumor and antimetastatic activity, which was further enhanced by rolipram. CONCLUSIONS:Overall, our findings support hypoxia-targeted combination approaches and provide a biological rationale for combining HIF-1 inhibition with immune checkpoint blockade in breast cancer.
Glucocorticoids, most commonly dexamethasone, are widely used alongside breast cancer therapy to alleviate adverse effects of chemotherapy, particularly allergic reactions and nausea. However, growing evidence shows that the activation of the glucocorticoid receptor (GR) has context-dependent effects on tumour biology, with both tumour-suppressive and tumour-promoting consequences. This review summarises the molecular basis of GR signalling in breast cancer and its prognostic relevance across molecular subtypes. Particular emphasis is placed on ligand-dependent and ligand-independent GR activation, crosstalk with the oestrogen receptor and GR-regulated transcriptional programmes associated with tumour cell migration and therapy resistance. Overall, the available evidence suggests that the use of glucocorticoids in triple-negative breast cancer is not biologically neutral. Assessment of GR using methods such as routine immunohistochemistry may add future value for patient's stratification for GR-targeted therapy and could inform more personalised supportive treatment and follow-up strategies; however, these approaches require prospective validation before clinical implementation.
