A unique molecule from starfish shows promise in killing tough prostate cancer cells and boosting chemotherapy effects, offering new hope for tackling treatment-resistant disease.
In a recent study published in the journal Scientific Reports, a group of researchers tested the anticancer efficacy, mechanisms, and combinatorial value of pacificusoside C (PaC) and cucumariosides C1 (CuC1)/CuC2 in resistant prostate-cancer models.
Background
More than 1.3 million men are diagnosed with prostate cancer every year, making it one of the five deadliest malignancies for males. Androgen deprivation therapy (ADT) plus androgen receptor (AR) pathway inhibitors (ARPIs) buys time, yet most tumors become drug-resistant, castration-resistant, or aggressive variant prostate cancer (AVPC) within a few years.
Key resistance programs like nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), phosphatidylinositol 3-kinase/protein kinase B/ B/mechanistic target of rapamycin (PI3K/AKT/mTOR), and epithelial-to-mesenchymal transition (EMT) remain hard to silence.
Marine triterpene glycosides can disrupt cellular membranes at cytotoxic concentrations and modulate survival cascades at sub-lethal doses, hinting at an ocean-sourced solution. These compounds, which the starfish acquires through its diet of sea cucumbers rather than producing them itself, warrant preclinical work to assess their potential as therapeutic agents.
About the study
In the present study, PaC, CuC1, and CuC2 were purified from the starfish Solaster pacificus. Prostate cancer models included Lymph Node Carcinoma of the Prostate (LNCaP), Vertebral Cancer of the Prostate (VCaP), Case Western Reserve-22 Relapse Variant 1 (22Rv1), Prostate Cancer-3 (PC3) with its docetaxel-resistant derivative PC3-Docetaxel Resistant (DR), and DU-145 brain-metastatic prostate carcinoma (DU145).
Controls used Prostate Normal Tissue Epithelial cell line 2 (PNT2), Rowell Prostate Epithelial cell line 1 (RWPE-1), Medical Research Council cell strain 9 (MRC-9) fibroblasts, and Human Embryonic Kidney 293 cells expressing Simian Virus 40 large T antigen (HEK293T), all maintained under standard culture conditions.
Viability after 48 h of drug exposure was quantified with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and half-maximal inhibitory concentrations (IC50) were calculated by nonlinear regression. Absorbance was measured on an Infinite F200PRO reader, and one-way analysis of variance assessed significance. A calcein-acetoxymethyl ester efflux assay probed whether the glycosides inhibited or evaded P-glycoprotein (P-gp) transport in PC3-DR cells, with tariquidar and docetaxel as positive controls.
Serine/threonine kinase (STK) activity was profiled on PamStation-12 microarrays after a two-hour exposure of 22Rv1 cells to CuC1 at twice its IC50; phosphorylated-peptide patterns were analyzed in BioNavigator. This represents the first study examining triterpene glycosides' effects on the cancer cell kinome.
Drug-interaction landscapes were generated by co-treating PC3-DR and 22Rv1 cells with CuC1 plus cisplatin, carboplatin, docetaxel, or cabazitaxel; Zero Interaction Potency (ZIP) synergy scores were extracted with SynergyFinder 3.0. All experiments used three biological replicates and dimethyl sulfoxide (DMSO) vehicle controls.
Study results
CuC1 was the most potent glycoside, as across six prostate-cancer lines its IC50 values spanned 0.25-5.7 µM, whereas PaC and CuC2 required higher doses. Hormone-refractory PC3 and DU145 cells were as sensitive as androgen-dependent LNCaP cells, and docetaxel-resistant PC3-DR cells showed a 3.6-fold loss of sensitivity, indicating minimal cross-resistance. However, it's important to note that CuC1's selectivity index of 0.7 and cisplatin's of 0.88 suggest that both compounds were slightly more cytotoxic to non-cancer cells, demonstrating no pronounced cancer-cell selectivity. PaC and CuC2 were even less discriminatory. Calcein-efflux assays demonstrated that CuC1 neither inhibited nor was exported by P-gp; tariquidar restored docetaxel but not CuC1 potency, confirming a P-gp-independent mechanism.
Short-term kinome profiling at sub-lethal doses (2 hours) revealed that CuC1 activated stress, necroptosis, metabolic, cytoskeletal, mitophagy, and immune-modulating STKs-Inhibitor of κB-Kinase alpha/beta / epsilon (IKKα/β/ε), mixed lineage kinase domain-like protein (MLKL), general control nonderepressible 2 (GCN2), 3-phosphoinositide-dependent protein kinase-1 (PDK1), Rho-associated protein kinase (RHOK), PTEN-induced kinase 1 (PINK1), and PITSLRE. The assay predicted, and Western blotting confirmed, specific inhibition of p38 and extracellular signal-regulated kinase 1/2 (ERK1/2) without changes in c-Jun N-terminal kinase (JNK1/2).
The researchers suggest this MAPK inhibition may be a secondary effect rather than direct molecular targeting. The paper notes that taxane-resistant cells have altered cholesterol metabolism, which could affect sensitivity to saponin-like compounds, though the specific mechanism linking this to MAPK inhibition remains speculative. Persistent ERK1/2 and p38 activity drives taxane resistance, so this dual blockade suggested a combinatorial value.
Synergy maps supported the hypothesis. In PC3-DR cells, CuC1 showed concentration-dependent interactions: markedly enhanced cisplatin, carboplatin, docetaxel, and cabazitaxel cytotoxicity at higher doses, yielding ZIP δ-scores > 10 across multiple dose pairs, while showing additive effects at lower concentrations; 22Rv1 cells showed primarily additive effects overall, with only minor antagonism at low-dose CuC1 plus cabazitaxel (δ value of -10.7).
CuC1 induced cleaved poly-(adenosine diphosphate-ribose) polymerase (PARP) and caspase-3 after 24 h, confirming apoptosis, while early 2-hour exposure was non-lethal, indicating that kinase remodeling precedes death. Despite matching cisplatin's limited selectivity index, CuC1 avoided heavy-metal deoxyribonucleic acid (DNA) cross-linking.
Unlike many saponins, the glycoside remained active in serum-containing medium and preserved membrane integrity at sub-lethal doses, enabling mechanistic assays. Its ability to trigger apoptotic and necroptotic markers suggests parallel death programs that could potentially curb resistance evolution.
Collectively, CuC1 delivers micromolar-to-sub-micromolar cytotoxicity across diverse prostate-cancer phenotypes, bypasses major resistance pumps, rewires central survival pathways, and shows dose-dependent synergization with first- and later-line chemotherapies.
Conclusions
PaC and CuC1/CuC2 from Solaster pacificus represent promising candidates for the anticancer arsenal against prostate tumors that evade current standards. In this early-stage in vitro study, CuC1 bypassed P-gp, blocked ERK1/2 and p38 mitogen-activated protein kinases, and amplified platinum- and taxane-based chemotherapy.
These actions translated into low-micromolar cytotoxicity across androgen-independent, DR, and AR-splice-variant-positive models, though with limited cancer-cell selectivity compared to non-malignant cells.
The multifaceted mechanism involving membrane effects plus coordinated stress-kinase rewiring may slow resistance evolution. Given the global burden of drug-refractory prostate cancer, further research, including in vivo safety and efficacy studies, is required before translating marine triterpene glycosides into potential combination-friendly therapeutics that could improve survival and preserve quality of life for affected patients.
Journal reference:
- Dyshlovoy, S. A., Hauschild, J., Kriegs, M., Hoffer, K., Burenina, O. Y., Strewinsky, N., Malyarenko, T. V., Kicha, A. A., Ivanchina, N. V., Stonik, V. A., Graefen, M., Bokemeyer, C., & von Amsberg, G. (2025). Anticancer activity of triterpene glycosides from the sea star Solaster pacificus. Sci Rep. 15. DOI: 10.1038/s41598-025-12914-7, https://www.nature.com/articles/s41598-025-12914-7