Biology subjects

Budak-Alpdogan, T.

Publications and source records attributed to Budak-Alpdogan, T..

3 recordsLinked to original sources

bioRxiv2025

Novel Pan-ALDH Inhibitor KS100 Effectively Targets ALDH+/CD138- Stem-like Cells to Overcome Relapse in Multiple Myeloma

Multiple myeloma (MM), a clonal plasma cell disorder is the second most frequent hematological malignancy in the United States. This malignancy is characterized by a series of symptoms such as bone lesions, hypercalcemia, renal failure, and anemia. The current clinical drugs in the market are successful in treating multiple myeloma patients into remission but does not address relapse where a more aggressive phenotype of the cancer remains untreatable. We hypothesize that a small subset of multiple myeloma stem-like cells (MMSLCs) that overexpress aldehyde dehydrogenases (ALDH+) is the cause of the relapse. Overexpression of ALDH bolsters drug resistance via detoxification and stemness via the retinoic acid signaling pathway. The phenotype of MMSLCs is not yet known for certainty but there are a few well established markers such CD138 negative (CD138neg) cells that are known to overexpress ALDH. In this study, we target regular MM cells and bortezomib resistant ALDH+/CD138neg MMSLCs with a novel, potent, pan-ALDH inhibitor, KS100. Here we report KS100 effectively lowered ALDH expression in regular and bortezomib resistant ALDH+/CD138neg cells, MM cell viability as well as proteins associated with MMSLCs. Most importantly we showed that KS100 lowered ALDH+ populations in regular, bortezomib resistant and CD138neg cells via ALDEFLUOR assay.

molecular biology↗

bioRxiv2023

A new efficacious Mcl-1 inhibitor maximizes bortezomib and venetoclax responsiveness in resistant multiple myeloma cells

Despite a record number of clinical studies investigating various anti-cancer drugs, the 5-year survival rate for multiple myeloma (MM) patients in the United States is only 55%, and nearly all patients relapse. Poor patient outcomes demonstrate that myeloma cells are "born to survive," which means they can adapt and evolve following treatment. As a result, new therapeutic approaches to combat this survival mechanism and target treatment-resistant malignant cells are required. Mcl-1, an anti-apoptotic protein, is required for the development of MM and resistance to therapy. This study looks at the possibility of KS18, a Mcl-1 inhibitor derived from pyoluteorin, to treat resistant MM. We show that KS18 inhibits Mcl-1 selectively and promotes post-translational modifications, resulting in UPS-dependent Mcl-1 degradation. Our findings show that KS18-induced Mcl-1 degradation results in caspase-dependent apoptosis. Importantly, KS18 triggered apoptosis in MM patient samples and bortezomib-resistant cells, synergizing with venetoclax to boost apoptosis. Furthermore, KS18 inhibits colony formation in bortezomib-resistant cells. KS18 treated NSG mice displayed significant tumor shrinkage without significant toxicity after four weeks of therapy with a single acceptable dose each week, indicating its powerful anti-neoplastic and anti-resistance characteristics. This study strongly implies that KS18 may treat MM and provide new hope to patients who are experiencing recurrence or resistance. Key pointsO_LIGiven that KS18 is a robust Mcl-1 inhibitor that targets Mcl-1 efficiently, it has the potential to be a novel treatment for multiple myeloma. C_LIO_LIKS18 has shown promise in re-sensitizing myeloma cells to chemotherapy as well as in overcoming resistance to bortezomib, venetoclax, and ABT-737. C_LI

pharmacology and toxicology↗

bioRxiv2022

Development of a Novel Bruton's Tyrosine Kinase Inhibitor that exerts Anti-Cancer Activities Potentiates Response of Chemotherapeutic Agents In Multiple Myeloma Stem Cell-Like Cells

Despite recent improvements in multiple myeloma (MM) treatment, MM remains an incurable disease and most patients experience a relapse. The major reason for myeloma recurrence is the persistent stem cell-like population. It has been demonstrated that overexpression of Brutons tyrosine kinase (BTK) in MM stem cell-like cells is correlated with drug resistance and poor prognosis. We have developed a novel small BTK inhibitor, KS151, which is unique compared to other BTK inhibitors. Unlike ibrutinib, and the other BTK inhibitors such as acalabrutinib, orelabrutinib, and zanubrutinib that covalently bind to the C481 residue in the BTK kinase domain, KS151 can inhibit BTK activities without binding to C481. This feature of KS151 is important because C481 becomes mutated in many patients and causes drug resistance. We demonstrated that KS151 inhibits in vitro BTK kinase activities and is more potent than ibrutinib. Furthermore, by performing a semi-quantitative, sandwich-based array for 71-tyrosine kinase phosphorylation, we found that KS151 specifically inhibits BTK. Our western blotting data showed that KS151 inhibits BTK signaling pathways and is effective against bortezomib-resistant cells as well as MM stem cell-like cells. Moreover, KS151 potentiates the apoptotic response of bortezomib, lenalidomide, and panobinostat in both MM and stem cell-like cells. Interestingly, KS151 inhibits stemness markers and is efficient in inhibiting Nanog and Gli1 stemness markers even when MM cells were co-cultured with bone marrow stromal cells (BMSCs). Overall, our results show that we have developed a novel BTK inhibitor effective against the stem cell-like population, and potentiates the response of chemotherapeutic agents.

molecular biology↗