Doxorubicin (DOX) is a widely used chemotherapy drug that can cause significant cardiotoxicity, limiting its clinical application. This study aimed to investigate the potential protective effects of topiramate (TPM) and spirulina (SP), either alone or in combination, in preventing DOX-induced cardiotoxicity. Adult Sprague Dawley rats were divided into five groups, including a normal control group and groups receiving DOX alone, DOX with TPM, DOX with SP, or DOX with a combination of TPM and SP. Cardiotoxicity was induced by administering DOX intraperitoneally at a cumulative dose of 16 mg/kg over 4 weeks. TPM and/or SP administration started 1 week before DOX treatment and continued for 35 days. Body weight, serum markers of cardiac damage, oxidative stress and inflammatory parameters were assessed. Histopathological and immunohistochemical examinations were performed on cardiac tissues. Results showed that TPM and SP monotherapy led to significant improvements in serum levels of cardiac markers, decreased oxidative stress, reduced fibrosis-related growth factor levels, increased antioxidant levels, and improved histopathological features. SP demonstrated more prominent effects in comparison to TPM, and the combination of TPM and SP exhibited even more pronounced effects. In conclusion, TPM and SP, either alone or in combination, hold promise as therapeutic interventions for mitigating DOX-induced cardiotoxicity.

Disease heterogeneity across a diverse patient cohort poses challenges to cancer drug development due to inter-patient variability in treatment responses. However, current preclinical models fail to depict inter-patient tumor heterogeneity, leading to a high failure rate when translating preclinical leads into clinical successes. We integrated the expression profiles of prostate cancer (PC) lines and castration-resistant PC (CRPC) patient tumors to identify cell-lines that transcriptomically match distinct tumor subtypes in a clinical cohort. Representative cell-lines were co-cultured to create “mixed-cell” models depicting inter-patient heterogeneity in CRPC, which were employed to assess drug combinations. When drug combinations previously tested in CRPC clinical cohorts were assessed to establish proof of concept, in vitro responses measured in our models concurred with their known clinical efficacy. Additionally, novel drug combinations computationally predicted to be efficacious in heterogeneous tumors were evaluated. They demonstrated preclinical efficacy in the mixed-cell models, suggesting they will likely benefit heterogeneous patient cohorts. Furthermore, we showed that the current practice of screening cell-lines/xenografts separately and aggregating their responses, failed to detect their efficacy. We believe that the application of our models will enhance the accuracy of preclinical drug assessment, thereby improving the success rate of subsequent clinical trials.

Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous subtype of breast cancer with limited treatment options. Our previous work explored repurposing selinexor, an XPO1 inhibitor, as a novel therapeutic option for TNBC. To enhance its efficacy, this study aimed to identify beneficial combination therapies with selinexor and experimentally evaluate their effects in TNBC. Using the computational tool IDACombo, we nominated drugs predicted to improve the efficacy of XPO1 inhibition. The top candidate, parthenolide, was tested in vitro using three transcriptionally distinct TNBC cell lines. Fluorescently labeled cells were co-cultured and treated with selinexor, parthenolide, or their combination. Growth inhibition was assessed across the mixed population and by individual cell line after 96 h, and potential synergy was evaluated using Combenefit. While selinexor and parthenolide monotherapy inhibited the growth of TNBC subtypes, the combination was more effective in suppressing the overall cell population. Synergistic interactions between the two agents were observed in specific TNBC lines but not all, reflecting the combination effect in heterogeneous TNBC patients. Our findings suggest the selinexor–parthenolide combination as a potential therapeutic strategy for TNBC, warranting further investigation. Our study also demonstrates the value of integrative computational–experimental approaches in guiding heterogeneity-informed drug combinations for preclinical evaluation.