BP-M345, a New Diarylpentanoid with Promising Antimitotic Activity

Previously, we reported the in vitro growth inhibitory effect of diarylpentanoid BP-M345 on human cancer cells. Nevertheless, at that time, the cellular mechanism through which BP-M345 exerts its growth inhibitory effect remained to be explored. In the present work, we report its mechanism of action on cancer cells. The compound exhibits a potent tumor growth inhibitory activity with high selectivity index. Mechanistically, it induces perturbation of the spindles through microtubule instability. As a consequence, treated cells exhibit irreversible defects in chromosome congression during mitosis, which induce a prolonged spindle assembly checkpoint-dependent mitotic arrest, followed by massive apoptosis, as revealed by live cell imaging. Collectively, the results indicate that the diarylpentanoid BP-M345 exerts its antiproliferative activity by inhibiting mitosis through microtubule perturbation and causing cancer cell death, thereby highlighting its potential as antitumor agent.

Curcumin Sensitizes Prolactinoma to Bromocriptine by Activating the ERK/EGR1 and Inhibiting AKT/GSK3β Signaling Pathway

Although bromocriptine (BRC) as first-line drugs are recommended for treating patients with prolactinoma, a minority of patients with prolactinoma resistance to BRC. Moreover, our previous study showed that the difference in drug sensitivity in BRC- treated rat prolactinoma cells, MMQ cells are more resistant to BRC, and GH3 cells are more sensitive to BRC. Curcumin (Cur) has been shown to inhibit proliferation of prolactinoma cell lines. The aim of this study is to further investigate whether Cur could enhance the growth-inhibitory effect of BRC resistance on prolactinoma cell lines and its possible mechanism. CCK-8 kit was used to test cell growth. Cell-cycle analysis and apoptosis was performed by flow cytometry. Electron microscopy was used to test autophagosome. The mRNA expression profiles were analysed using the Affymetrix Gene-Chip array. Western blotting was used to test protein expression. Our data showed that Cur enhanced the growth-inhibitory effect of BRC on GH3 and MMQ cell proliferation. BRC and Cur both induced cell apoptosis, and Cur could significantly increase the apoptosis of BRC on pituitary adenoma cells through the ERK/EGR1 signaling pathway. Moreover, Cur could enhance the autophagic cell death (ACD) of BRC on tumor cell by inhibiting the AKT/GSK3β signaling pathway. The same results were confirmed in vivo study. Taken together, Cur sensitizes rat pituitary adenoma cell to BRC by activating the ERK/EGR1 and inhibiting AKT/GSK3β signaling pathway.

NLRR1 Is a Potential Therapeutic Target in Neuroblastoma and MYCN-Driven Malignant Cancers

Receptor tyrosine kinases (RTKs) receive different modulation before transmitting proliferative signals. We previously identified neuronal leucine-rich repeat 1 (NLRR1) as a positive regulator of EGF and IGF-1 signals in high-risk neuroblastoma cells. Here, we show that NLRR1 is up-regulated in various adult cancers and acts as a key regulator of tumor cell proliferation. In the extracellular domains of NLRR1, fibronectin type III (FNIII) domain is responsible for its function to promote cell proliferation. We generated monoclonal antibodies against the extracellular domains of NLRR1 (N1mAb) and screened the positive N1mAbs for growth inhibitory effect. The treatment of N1mAbs reduces tumor cell proliferation in vitro and in vivo, and sensitizes the cells to EGFR inhibitor, suggesting that NLRR1 is a novel regulatory molecule of RTK function. Importantly, epitope mapping analysis has revealed that N1mAbs with growth inhibitory effect recognize immunoglobulin-like and FNIII domains of NLRR1, which also indicates the importance of FNIII domain in the function of NLRR1. Thus, the present study provides a new insight into the development of a cancer therapy by targeting NLRR1 as a modulator of proliferative signals on cellular membrane of tumor cells.

Curcumin sensitizes prolactinoma to bromocriptine by activating the ERK/EGR1 and inhibiting AKT/GSK3β signaling pathway

Background Although bromocriptine (BRC) as first-line drugs are recommended for treating patients with prolactinoma, a minority of patients with prolactinoma resistance to BRC. Curcumin (Cur) has been shown to inhibit proliferation of prolactinoma cell lines. The aim of this study is to investigate whether Cur could enhance the growth-inhibitory effect of BRC resistance on prolactinoma cell lines and its possible mechanism. Methods CCK-8 kit was used to test cell growth. Cell-cycle analysis and apoptosis was performed by flow cytometry. Electron microscopy was used to test autophagosome. The mRNA expression profiles were analysed using the Affymetrix Gene-Chip array. Western blotting was used to test protein expression. The SPSS version 17.0 software was applied for statistical analysis. Results Our data showed that Cur enhanced the growth-inhibitory effect of BRC on GH3 and MMQ cell proliferation. BRC and Cur both induced cell apoptosis, and Cur could significantly increase the apoptosis of BRC on pituitary adenoma cells through the ERK/EGR1 signaling pathway. Moreover, Cur could enhance the autophagic cell death (ACD) of BRC on tumor cell by inhibiting the AKT/GSK3β signaling pathway. The same results were confirmed in vivo study. Conclusion Cur sensitizes rat pituitary adenoma cell to BRC by activating the ERK/EGR1 and inhibiting AKT/GSK3β signaling pathway.

The inhibitory effect of cisplatin, paclitaxel, and pemetrexed on the growth of PC9GR cells resistant to NK cell-mediated cytotoxicity during the COVID-19 pandemic.

e15009 Background: Lung cancer patients have a significantly higher risk of contracting COVID-19, and interactions with the healthcare system during cancer therapy can put patients at risk. Preliminary studies in COVID-19 patients with severe disease found a reduction in the number and function of natural killer (NK) cells. Other studies in COVID-19 patients reported acute respiratory distress syndrome (ARDS) due to the extreme release of inflammatory cytokines. Besides, adverse effects of chemotherapy, such as chemotherapy resistance and the escalation of cellular senescence can worsen the condition of patients with COVID-19. Considering these facts, we evaluated the growth-inhibitory effects of three commonly used chemotherapy drugs, cisplatin, pemetrexed, and paclitaxel, in gefitinib-resistant non-small cell lung cancer (PC9GR) cells and investigated the underlying mechanism. Methods: In this study, flow cytometry (FCM) was used to profile the activity and function of human NK cells. An enzyme-linked immunosorbent assay (ELISA) was performed to quantify cytokine levels. PC9GR cells were treated with cisplatin, paclitaxel, or pemetrexed as monotherapy for 72 h and then evaluated with a cell viability assay, a reactive oxygen species (ROS) assay, a terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, SA-β-Gal staining, and Western blotting. Results: We demonstrated that NK cell dysfunction was linked to the reduced NK-mediated elimination of PC9GR cells. The PC9GR cells showed the marked secretion of IL-6, IL-8 and VEGF cytokines, which was connected to the activation of the inhibitory signaling pathway of NK cells. We found that paclitaxel was the most potent growth inhibitor, cisplatin had an intermediate growth inhibitory effect, and pemetrexed induced a minimal growth inhibitory effect in PC9GR cells. These growth inhibitory effects were observed to be associated with ROS-mediated DNA damage, which led to the activation of apoptotic caspases. Surprisingly, paclitaxel was the strongest remover of senescent cells; pemetrexed had an intermediate effect, and cisplatin removed the lowest number of senescent cells. Conclusions: In light of these findings, paclitaxel may have a better therapeutic effect than cisplatin or pemetrexed on PC9GR cells, suggesting that paclitaxel could offer a novel therapeutic approach for the treatment of gefitinib-resistant non-small cell lung cancer during the COVID-19 pandemic.

The long non-coding RNA MIR31HG regulates the senescence associated secretory phenotype

Oncogene-induced senescence provides a barrier against malignant transformation. However, it can also promote cancer through the secretion of a plethora of factors released by senescent cells, called the senescence associated secretory phenotype (SASP). We have previously shown that in proliferating cells, nuclear lncRNA MIR31HG inhibits p16/CDKN2A expression through interaction with polycomb repressor complexes and that during BRAF-induced senescence, MIR31HG is overexpressed and translocates to the cytoplasm. Here, we show that MIR31HG regulates the expression and secretion of a subset of SASP components during BRAF-induced senescence. The SASP secreted from senescent cells depleted for MIR31HG fails to induce paracrine invasion without affecting the growth inhibitory effect. Mechanistically, MIR31HG interacts with YBX1 facilitating its phosphorylation at serine 102 (p-YBX1S102) by the kinase RSK. p-YBX1S102 induces IL1A translation which activates the transcription of the other SASP mRNAs. Our results suggest a dual role for MIR31HG in senescence depending on its localization and points to the lncRNA as a potential therapeutic target in the treatment of senescence-related pathologies.