Parthenolide enhances imatinib activity in gastrointestinal stromal tumor models through stress-associated apoptosis

Imatinib remains a mainstay of treatment for gastrointestinal stromal tumors (GISTs), yet responses may be incomplete or short-lived. We examined whether parthenolide (PTL) enhances imatinib activity in GIST models and characterized the cellular changes associated with combined treatment. Public GIST transcriptomic datasets were analyzed as hypothesis-generating resources. GIST-T1 and GIST-882 cells were treated with PTL, imatinib, or their combination. Cell growth, migration, colony formation, apoptosis, reactive oxygen species, mitochondrial function and ultrastructure, ER-stress-associated proteins, and autophagy-associated markers were assessed. Antitumor activity was further examined in a GIST-T1 xenograft model. PTL and imatinib each inhibited GIST cell growth in a concentration-dependent manner. At the selected concentrations, the combination produced greater and more sustained suppression of cell viability, migration, and colony formation than either monotherapy. TUNEL staining and Annexin V-FITC/PI analysis showed increased apoptosis, accompanied by lower Bcl-2 expression and a higher Bax/Bcl-2 ratio. Combined treatment also increased DCF fluorescence, reduced mitochondrial membrane potential, caused mitochondrial ultrastructural abnormalities, increased p-IRE1α/IRE1α and CHOP, and altered PINK1, LC3B, and Beclin-1. In vivo, the combination showed the slowest mean tumor growth and the lowest endpoint tumor weight, without greater body weight loss than imatinib alone. PTL enhanced imatinib activity in imatinib-responsive GIST models. This effect was accompanied by apoptotic, oxidative, mitochondrial, ER stress-associated, and autophagy-associated changes; however, their causal relationships remain to be established.