Biology subjects

Saki, M.

Publications and source records attributed to Saki, M..

5 recordsLinked to original sources

bioRxiv2025

Repurposing Quetiapine as an Adjuvant Therapeutic Agent for Triple-Negative Breast Cancer

PurposeTriple-negative breast cancer (TNBC) lacks actionable molecular targets, so treatment primarily relies on cytotoxic chemotherapy and radiotherapy, yet relapse, resistance, and metastasis still drives poor long-term survival. Dopamine signaling has recently been linked to tumor aggressiveness, and dopaminel1lreceptor antagonists have shown preclinical benefit in other cancers. We therefore evaluated quetiapine (QTP), an FDAl1lapproved DRD2/DRD3 antagonist, as a therapeutic adjunct in TNBC. MethodsSUM159l1lPT, BTl1l549, and MDAl1lMBl1l231 cells were treated with QTP alone or combined with radiation or standard agents (doxorubicin, paclitaxel, 5l1lfluorouracil). Clonogenic and mammosphere assays measured proliferative and selfl1lrenewal potential. Annexin V/propidiuml1liodide flow cytometry quantified apoptosis, and {gamma}l1lH2AX immunofluorescence tracked DNA doublel1lstrand breaks and repair kinetics. Transwell assays assessed migration of untreated bulk cells and radiationl1lsurviving subclones. ResultsQTP significantly reduced clonogenicity and self-renewal in all TNBC models tested, both alone and in combination with radiation or chemotherapy. In apoptosis assays, QTP treatment induced a marked increase in early and late apoptotic cell populations. QTP also promoted DNA double-strand break formation and delayed repair, as indicated by persistent {gamma}-H2AX foci at 24 hours post-treatment. Additionally, QTP impaired the migratory capacity of both untreated and radiation-surviving cells. Combination treatments with QTP and doxorubicin produced synergistic effects, resulting in complete loss of colony-forming ability and mammosphere formation. ConclusionThe data presented support the repurposing of quetiapine as an adjuvant therapeutic agent alongside radiotherapy and/or chemotherapy in TNBC. By targeting apoptosis, DNA repair, and cancer cell migration, QTP offers a novel, multi-faceted approach to improve outcomes in this high-risk breast cancer subtype.

cancer biology↗

bioRxiv2025

Combined quetiapine and radiation therapy approach to treat mesothelioma-initiating cells and increase survival in a mouse model of mesothelioma

IntroductionMalignant pleural mesothelioma (MPM) is a rare thoracic cancer associated with poor prognosis and low survival rates. In solid cancers, repurposed dopamine receptor antagonists have been shown to have anti-cancer effects. Moreover, in combination with radiotherapy, quetiapine (QTP), a dopamine (D) 2/3 receptor antagonist, has been shown to interfere with self-renewal capacity in glioma-initiating cells and increase survival in mouse models of glioblastoma. In this study we explore combined treatment effects in MPM. MethodsUsing mesothelioma cell lines, MSTO-211H, H2052, and H2452, and a MSTO-211H-derived orthotopic xenograft mouse model of MPM we examined how QTP combined with radiation affects mesothelioma-initiating cells (MICs) in vitro and survival in vivo. Subsequently, bulk and single cell RNA sequencing was used to characterize the transcriptomic landscape of MSTO-211H treated with combined radiation and QTP. ResultsWe demonstrate that combining QTP with radiation reduces MIC self-renewal capacity and stem cell frequency. In vivo, this combination therapy significantly extends the median survival of mesothelioma-bearing mice. Clonogenic survival assays revealed that QTP does not enhance radiosensitivity in the tested mesothelioma cell lines. Sequencing data revealed, combined treatment downregulated cell cycle and proliferation pathways, depleted cancer stem cells, and increased cellular senescence. ConclusionTaken together, our study highlights the therapeutic potential of radiation with QTP in the treatment of MPM.

cancer biology↗

bioRxiv2020

Combined Treatment with Dopamine Receptor Antagonists and Radiation Creates a Metabolic Vulnerability in Mouse Models of Glioblastoma

BackgroundGlioblastoma is the deadliest brain tumor in adults and the standard-of-care consists of surgery followed by radiation and treatment with temozolomide. Overall survival times for patients suffering from glioblastoma are unacceptably low indicating an unmet need for novel treatment options. MethodsUsing patient-derived glioblastoma lines and mouse models of glioblastoma we test the effect of radiation and the dopamine receptor antagonist on glioblastoma self-renewal in vitro and survival in vivo. A possible resistance mechanism is investigated using RNA-Sequencing. ResultsTreatment of glioma cells with the dopamine receptor antagonist quetiapine reduced glioma cell self-renewal in vitro and combined treatment of mice with quetiapine and radiation prolonged the survival of glioma-bearing animals. The combined treatment induced the expression of genes involved in cholesterol biosynthesis. This rendered the tumors vulnerable to simultaneous treatment with atorvastatin and further significantly prolonged the survival of the animals. ConclusionsOur results indicate high efficacy of a triple combination of quetiapine, atorvastatin and radiation against glioblastoma without increasing the toxicity of radiation. With both drugs readily available for clinical use our study could be rapidly translated into a clinical trial.

neuroscience↗

bioRxiv2020

1--4-phenylpiperazine Treatment After Brain Irradiation Preserves Cognitive Function in Mice

BackgroundNormal tissue toxicity to the CNS is an inevitable consequence of a successful radiotherapy of brain tumors or cancer metastases to the CNS. Cranial irradiation commonly leads to neurocognitive deficits that manifest months or years after treatment. Mechanistically, radiation-induced loss of neural stem/progenitor cells, neuro-inflammation and de-myelinization are contributing factors that lead to progressive cognitive decline. MethodsThe effects of Compound #5 on irradiated murine neurospheres, microglia cells and patients-derived gliomaspheres were assessed in sphere-formation assays, flow cytometry and IL-6 ELISAs, Activation of the Hedgehog pathway was studied by qRT-PCR. The in vivo effects of Compound #5 were analyzed using flow cytometry, sphere-formation assays, immune-histochemistry, behavioral testing and an intracranial mouse model of glioblastoma. ResultsWe report that 1-[(4-Nitrophenyl)sulfonyl]-4-phenylpiperazine (Compound #5) mitigates radiation-induced normal tissue toxicity in the brains of mice. Compound #5 treatment significantly increased the number of neural stem/progenitor cells after brain irradiation in female animals, inhibited radiation-induced microglia activation and expression of the pro-inflammatory cytokine interleukin-6. Behavioral testing revealed that treatment with Compound #5 after radiotherapy successfully mitigates radiation-induced decline in motor, sensory and memory function of the brain. In mouse models of glioblastoma, Compound #5 showed no toxicity and did not interfere with the growth-delaying effects of radiation. ConclusionsWe conclude that Compound #5 has the potential to mitigate cognitive decline in patients undergoing partial or whole brain irradiation without promoting tumor growth and that the use of this compound as a radiation mitigator of radiation late effects on the CNS warrants further investigation. Importance of the StudySuccessful radiotherapy of CNS malignancies inevitably lead to cognitive decline in cancer survivors and treatment options to mitigate this side effect are limited. We present evidence that a piperazine compound can prevent cognitive decline in mice after total brain irradiation without compromising the antitumor effect of radiation, suggesting that this compound could be used to mitigate radiation side effects in brain tumor patients undergoing radiotherapy.

neuroscience↗

bioRxiv2019

The Dopamine Receptor Antagonist TFP Prevents Phenotype Conversion and Improves Survival in Mouse Models of Glioblastoma

Glioblastoma (GBM) is the deadliest adult brain cancer and all patients ultimately succumb to the disease. Radiation therapy (RT) provides survival benefit of 6 months over surgery alone but these results have not improved in decades. We report that radiation induces a glioma-initiating cell phenotype and we have identified trifluoperazine (TFP) as a compound that interferes with this phenotype conversion. TFP caused loss of radiation-induced Nanog mRNA expression, activation of GSK3 with consecutive post-translational reduction in p-Akt, Sox2 and {beta}-catenin protein levels. TFP did not alter the intrinsic radiation sensitivity of glioma-initiating cells (GICs). Continuous treatment with TFP and a single dose of radiation reduced the number of GICs in vivo and prolonged survival in syngeneic and patient-derived orthotopic xenograft (PDOX) mouse models of GBM. Our findings suggest that combination of a dopamine receptor antagonist with radiation enhances the efficacy of RT in GBM by preventing radiation-induced phenotype conversion of radiosensitive non-GICs into treatment resistant, induced GICs. SignificanceGBM is the most common and most deadly adult brain cancer. The current standard-of-care is surgery followed by RT and temozolomide, which results in a median survival time of only 15 months. The efficacy of chemotherapies and targeted therapies in GBM is very limited because most of these drugs do not pass the blood-brain-barrier. Ultimately, all patients succumb to the disease. Our study describes radiation-induced cellular plasticity as a novel resistance mechanism in GBM. We identified a dopamine receptor antagonist as a readily available, FDA-approved drug known to penetrate the blood-brain-barrier which prevents phenotype conversion of glioma cells into glioma-initiating cells and prologs survival in mouse models of GBM, thus suggesting that it will improve the efficacy of RT without increasing toxicity.

neuroscience↗