Cancer metastasis and recurrence remain a regular cause of postoperative death in patients, implying that extra consolidation treatment strategies are needed. Here, a cuproptosis nanoprodrug, termed as Lipo@CP@DQ NPs, is developed to initiate self-promoted cascade reactions to achieve the combinational effect of cuproptosis, in situ chemotherapy, and oxidative stress amplification for effectively suppressing tumor recurrence and metastasis after postoperative treatment. Lipo@CP@DQ NPs are fabricated by loading copper peroxides (Cu₂O₂, CP) and hydrogen peroxide (H₂O₂)-repsonsive prodrug DQ into liposomal nanoparticles. Lipo@CP@DQ NPs rapidly dissociate in the acidic tumor microenvironment to release copper ions, H₂O₂, and prodrug DQ. Subsequently, the excessive accumulation of Cu ions induces cuproptosis and produces highly cytotoxic hydroxyl radicals (•OH). Meanwhile, the self-supplied H₂O₂ catalyzes the decomposition of DQ to diethyldithiocarbamate (DTC), which is chelated with self-supplied Cu ions to form the anticancer compound, Cu(DTC)₂. The another decomposition product, quinone methide (QM), acts as a glutathione (GSH) scavenger for oxidative stress amplification. The synergistic effect of Lipo@CP@DQ NPs-mediated cuproptosis, in situ chemotherapy, and oxidative stress amplification effectively inhibits the growth and postoperative recurrence of triple-negative breast cancer. This work furnishes a strategy for developing cuproptosis-based nanomedicines for effective antitumor treatment after surgery.

01 Jun 2025·Life Sciences

Metabolic reprogramming and synergistic cytotoxicity of genistein and chemotherapy in human breast cancer cells

Article

Author: Noriega, Lilia G ; Acevedo-Carabantes, Joshua Ayork ; Granados-Portillo, Omar ; Vargas-Castillo, Ariana ; Morales-Bárcenas, Rocío ; Torres, Nimbe ; Juarez, Mandy ; Tovar, Armando R ; Tobón-Cornejo, Sandra ; Schcolnik-Cabrera, Alejandro ; Chávez-Blanco, Alma

Breast cancer (BCa) is a heterogeneous disease, initially responsive to hormone therapy but often developing resistance to both hormonal and chemotherapy treatments. Novel therapeutic strategies are needed for drug-resistant BCa. Genistein, a phytoestrogen structurally similar to estrogen, competes with estrogen for receptor binding and exhibits anti-cancer effects. In this study, we investigated the cellular and metabolic impacts of genistein, alone or in combination with chemotherapy, in two human BCa cell lines-one estrogen receptor-positive (ER+) and one estrogen receptor-negative (ER-). We observed a strong synergistic effect on cell viability at low concentrations of genistein and chemotherapy, resulting in reduced clonogenic capacity and impaired cell migration. Genistein alone modulated cellular energy metabolism, notably reducing ATP production in MCF7 (ER+) cells. This metabolic shift was linked to a decreased dependence on fatty acids for energy, coupled with a decrease in the rate-limiting mitochondrial translocase CPT1 required for fatty acid oxidation, alongside with an increase in intracellular fatty acid levels. While the most significant changes occurred in ER+ cells, ER- cells also showed responses to genistein treatment. Collectively, our findings suggest that low genistein concentrations, in combination with conventional chemotherapy, induces synergistic anti-cancer effects, promoting cellular senescence.

01 Apr 2025·Journal of Biological Chemistry

Derivation of human trophoblast stem cells from placentas at birth

Article

Author: Jabeen, Mahe ; San Miguel, Adriana ; Rao, Balaji M ; Britt, John W ; Karakis, Victoria

Human trophoblast stem cells (hTSCs) have emerged as a powerful tool for modeling the placental cytotrophoblast (CTB) in vitro. hTSCs were originally derived from CTBs of the first trimester placenta or blastocyst-stage embryos in trophoblast stem cell medium (TSCM) that contains epidermal growth factor (EGF), the glycogen synthase kinase-beta (GSK3β) inhibitor CHIR99021, the transforming growth factor-beta (TGFβ) inhibitors A83-01 and SB431542, valproic acid (VPA), and the Rho-associated protein kinase (ROCK) inhibitor Y-27632. Here we show that hTSCs can be derived from CTBs isolated from the term placenta, using TSCM supplemented with a low concentration of mitochondrial pyruvate uptake inhibitor UK5099 and lipid-rich albumin (TUA medium). Notably, hTSCs could not be derived from term CTBs using TSCM alone, or in the absence of either UK5099 or lipid-rich albumin. Strikingly, hTSCs cultured in TUA medium for a few passages could be transitioned into TSCM and cultured thereafter in TSCM. hTSCs from term CTBs cultured in TUA medium as well as those transitioned into and cultured in TSCM thereafter could be differentiated to the extravillous trophoblast and syncytiotrophoblast lineages and exhibited high transcriptome similarity with hTSCs derived from first trimester CTBs. We anticipate that these results will enable facile derivation of hTSCs from normal and pathological placentas at birth with diverse genetic backgrounds and facilitate in vitro mechanistic studies in trophoblast biology.

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Indication	Highest Phase	Country/Location	Organization	Date
Non-Small Cell Lung Cancer	Discovery	United States	Bristol University	19 Jun 2024

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