Metabolic heterogeneity resulting from the intra-tumoral heterogeneity mediates massive adverse outcomes of tumor therapy, including chemotherapeutic resistance, but the mechanisms inside remain largely unknown. Here, we find that the de novo pyrimidine synthesis pathway determines the chemosensitivity. Chemotherapeutic drugs promote the degradation of cytosolic Carbamoyl-phosphate synthetase II, Aspartate transcarbamylase, and Dihydroorotase (CAD), an enzyme that is rate-limiting for pyrimidine synthesis, leading to apoptosis. We also find that CAD needs to be cleaved by caspase-3 on its Asp1371 residue, before its degradation. Overexpressing CAD or mutating Asp1371 to block caspase-3 cleavage confers chemoresistance in xenograft and Cldn18-ATK gastric cancer models. Importantly, mutations related to Asp1371 of CAD are found in tumor samples that failed neoadjuvant chemotherapy and pharmacological targeting of CAD-Asp1371 mutations using RMY-186 ameliorates chemotherapy efficacy. Our work reveals the vulnerability of de novo pyrimidine synthesis during chemotherapy, highlighting CAD as a promising therapeutic target and biomarker.
© 2025. The Author(s).

Orostachys japonicus A. Berger (O. japonicus) is a perennial herb belonging to the Crassulaceae family that has been traditionally used to treat inflammation, fever, and poisoning. Although studies on the anticancer activity of O. japonicus have been conducted, its effect on virus-induced cancers has yet to be elucidated.
In the present study, we investigated the effects and mechanisms of action of the ethyl acetate fraction of O. japonicus extract (E-OJ) on the viability and apoptosis of HeLa cervical cancer cells.
The effect of E-OJ on HeLa cells was compared to that of kaempferol, quercetin, and gallic acid, which are components of O. japonicus. Treatment with E-OJ induced a concentration-dependent decrease in cell viability, as confirmed by MTS assay. Pretreatment with a broad-spectrum caspase inhibitor resulted in the recovery of cell viability. Western blot analysis was conducted to determine whether the induction of apoptosis was caspase-dependent. E-OJ induced apoptosis by increasing Bax/Bcl-2 ratio. Furthermore, it modulated the levels of cleaved caspase-3, -8, and -9, indicative of an impact on both the intrinsic and extrinsic pathways of apoptosis. Pretreatment with caspase inhibitors reduced caspase activity.
These results suggest that the anticancer activity of O. japonicus is mediated by caspases, resulting in a decrease in the viability of HeLa cells.
©2025 The Korean Nutrition Society and the Korean Society of Community Nutrition.

Despite recent therapeutic advances, the 5-year survival rate for adults with acute myeloid leukemia (AML) is poor and standard-of-care chemotherapy is associated with significant toxicity, highlighting the need for new therapeutic approaches. Recent work from our group and others established that the G protein-coupled estrogen receptor (GPER) is tumor suppressive in melanoma and other solid tumors. We performed a preliminary screen of human cancer cell lines from multiple malignancies and found that LNS8801, a synthetic pharmacologic agonist of GPER currently in early phase clinical trials, promoted apoptosis in human AML cells. Using human AML cell lines and primary cells, we show that LNS8801 inhibits human AML in preclinical in vitro models, while not affecting normal mononuclear cells. Although GPER is broadly expressed in normal and malignant myeloid cells, this cancer-specific LNS8801-induced inhibition appeared to be independent of GPER signaling. LNS8801 induced AML cell death primarily through a caspase-dependent apoptosis pathway. This was independent of secreted classical death receptor ligands, and instead required induction of reactive oxygen species (ROS) and activation of endoplasmic reticulum (ER) stress response pathways including IRE1α. These studies demonstrate a novel activity of LNS8801 in AML cells and show that targeting ER stress with LNS8801 may be a useful therapeutic approach for AML.
Previous work demonstrated that LNS8801 inhibits cancer via GPER activation, especially in solid tumors. Here we show that LNS8801 inhibits AML via GPER-independent mechanisms that include ROS induction and ER activation.
© 2023 The Authors; Published by the American Association for Cancer Research.

Searching for new strategies for effective elimination of human prostate cancer cells, we investigated the cooperative cytotoxic action of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and two platinum-based complexes, cisplatin or LA-12, and related molecular mechanisms. We demonstrated a notable ability of cisplatin or LA-12 to enhance the sensitivity of several human prostate cancer cell lines to TRAIL-induced cell death via an engagement of mitochondrial apoptotic pathway. This was accompanied by augmented Bid cleavage, Bak activation, loss of mitochondrial membrane potential, activation of caspase-8, -10, -9, and -3, and XIAP cleavage. RNAi-mediated silencing of Bid or Bak in Bax-deficient DU 145 cells suppressed the drug combination-induced cytotoxicity, further underscoring the involvement of mitochondrial signaling. The caspase-10 was dispensable for enhancement of cisplatin/LA-12 and TRAIL combination-induced cell death and stimulation of Bid cleavage. Importantly, we newly demonstrated LA-12-mediated enhancement of TRAIL-induced cell death in cancer cells derived from human patient prostate tumor specimens. Our results provide convincing evidence that employing TRAIL combined with cisplatin/LA-12 could contribute to more effective killing of prostate cancer cells compared to the individual action of the drugs, and offer new mechanistic insights into their cooperative anticancer action.

Melanoma, a cancer derived from melanocytes, is one of the most chemoresistant cancers and tends to metastasize. Once it metastasizes, the prognosis is poor. Even with the recent advancement of targeted therapy and immunotherapy, the prognosis remains discouraging. SR-T100, a Solanum incanum extract, shows anticancer effects against several cancers; however, its therapeutic efficacy against melanoma and established metastasis remains unknown. In this study, we showed that SR-T100 induces apoptosis, DNA damage, and G0/G1 cell cycle arrest in murine B16 melanoma cells in vitro. In vivo, intralesional injection of SR-T100 decreased the tumor size of the regional melanoma in the foot pad. Moreover, intraperitoneal injection of SR-T100 inhibited the growth and the number of established melanoma metastases in the lungs. Our study highlights SR-T100 as a potential novel treatment for established tumors from regional and metastatic melanoma.