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Recent evidences highlight the usefulness of small molecule (Histone deacetylase 4) HDAC4 inhibitors in the several preclinical paradigms. Major toxicity and mutagenicity issues associated with hydroxamate HDAC inhibitors, stimulated us to develop potent non‐hydroxamate inhibitors. In the present work a novel series of thiazolidinedione (TZD) derivatives with pyridine as cyclic linker and TZD ring as zinc binding group was designed and screened in a panel of isoenzymes of HDACs, wherein the most potent compounds exhibiting HDAC4 IC50‐values<5 μM were 5 v, 5 w, 5 y and 5 z (IC50=4.2±1 μM, 0.75±0.03 μM, 4.9±0.5 and 2.3±0.5 μM, respectively). The docking studies displayed the unique binding mode of this series of compound at active site of HDAC4, wherein TZD ring was indicated as zinc binding group. Further, 5 w and 5 y were found as the most potent antiproliferative agent in lymphoblastic leukemia (CCRF‐CEM) and breast cancer MDA‐MB‐231 cells. Compound 5 y was found to induce the apoptosis and DNA fragmentation of CEM cells. The western blotting analysis of 5 y also showed the presence of cleaved caspases supporting their apoptotic nature. Further, Class IIa (HDAC4) selectivity of 5 y was also supported by western blotting observations, wherein 5 y caused the accumulation of acetylated H3 but not of acetylated Tubulin. Thus, our findings endorse the further investigation of this series of compounds for their potential as targeted cancer therapeutic agents. [ABSTRACT FROM AUTHOR]

The potent antimalarial drug pyronaridine (PND) was tested for its potential as an anticancer drug. After exposing cancerous (17) and non-cancerous (2) cells to PND for 72 hr, PND was found to exhibit consistent and potent cytotoxic activity at low micromolar (μM) concentrations that ranged from 1.6 μM to 9.4 μM. Moreover, PND exerted a significant selective cytotoxicity index (SCI) on five out of seven breast cancer cell lines tested, with favorable values of 2.5 to 4.4, as compared with the non-cancerous breast MCF-10A cell line. By using the same comparison, PND exhibited a significant SCI on three out of four leukemia/lymphoma cell lines with promising values of 3.3 to 3.5. One breast cancer and one leukemia cell line were tested further in order to determine the likely mode of action of PND. PND was found to consistently elicit phosphatidylserine externalization, mitochondrial depolarization, and DNA fragmentation, in both the triple negative MDA-MB-231 breast cancer and HL-60 leukemia cell lines. In addition, PND treatment altered cell cycle progression in both cancer cells. Subsequent DNA mobility-shift assays, UV-Visible spectroscopic titrations, and circular dichroism (CD) experiments revealed that PND intercalates with DNA. The findings presented in this study indicates that PND induces apoptosis and interfered with cell cycle progression of cancer cell lines and these results indicate that this drug has the potential as a repurposed drug for cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) continues to have the second highest mortality amongst women in the United States after lung cancer. For 2021, the American Cancer Association predicted 281,550 new invasive breast cancer cases besides 49,290 new cases of non-invasive breast cancer and 43,600 deaths from the metastatic disease. A treatment modality is radiation therapy, which is given for local control as well as palliation of patient symptoms. The initial step of new drug development is in-vitro cell studies, which help describe new drug properties and toxicities. However, these models are not optimal, and better ones have yet to be determined. This study uses bioprinting technology to elucidate the sensitivity of tumor cells to the combination of palbociclib (PD) and letrozole (Let) treatment. We hypothesize that this technology could serve as a model to predict treatment outcomes more efficiently. Methods: The breast cancer cell lines MCF7 and MDA-MB-231 as well as the normal breast epithelial cell line, MCF-10A, were treated with PD-Let with and without radiotherapy (RT), and cell viability was compared in pairwise fashion for thermally inkjet bioprinted (TIB) and manually seeded (MS) cells. Results: In absence of radiation, the TIB MCF7 cells have 2.5 times higher viability than manually seeded (MS) cells when treated with 100 µM palbociclib and 10 µM letrozole, a 36% higher viability when treated with 50 µM palbociclib and 10 µM letrozole, and an 8% higher viability when treated with 10 µM palbociclib and 10 µM letrozole. With 10 Gy of radiation, TIB cells had a 45% higher survival rate than MS cells at the lowest palbociclib concentration and a 29% higher survival rate at the intermediate palbociclib concentration. Without radiation treatment, at a concentration of 10 μM PD-Let, TIB MDA-MB-231 cells show a 8% higher viability than MS cells when treated with 10 µM PD and 10 µM Let; at higher drug concentrations, the differences disappeared, but some 1.7% of the TIB MDA-MB-231 cells survived exposure to 150 μM of PD + 10 μM letrozole vs. none of the MS cells. These cells are more radiation sensitive than the other cell lines tested and less sensitive to the combo drug treatments. We observed an 18% higher survival of TIB MCF-10A cells without radiation treatment when exposed to 10 μM PD + 10 μM Let but no difference in cell survival between the two groups when radiation was applied. Independent of growth conditions, TIB cells did not show more resistance to radiation treatment than MS cells, but a higher resistance to the combo treatment was observed, which was most pronounced in the MCF-7 cell line. Conclusion: Based on these results, we suggest that TIB used in in-vitro models could be a feasible strategy to develop and/or test new anticancer drugs. [ABSTRACT FROM AUTHOR]