No abstract

Regorafenib, an oral small-molecule multi kinase inhibitor, is able to block Vascular Endothelial Growth Factor Receptors (VEGFR-1, 2, and 3), Platelet-Derived Growth Factor Receptors (PDGF), Fibroblast Growth Factor (FGF) receptor 1, Raf, TIE-2, and the kinases KIT, RET, and BRAF. Different studies have displayed its antitumor activity in several cancer models (both in vitro and in vivo), particularly in colorectal and gastrointestinal stromal cancers. The mechanism of resistance to regorafenib is largely unknown. In our investigation, we have generated regorafenib-resistant SW480 cells (Reg-R-SW480 cells) by culturing such cells with increasing concentration of regorafenib. Examination of intracellular signaling found that Akt signaling was activated in Reg-R-SW480 cells but not in wild-type SW480 cells, after regorafenib treatment as measured by Western Blot. The Notch pathway is a fundamental signaling system in the development and homeostasis of tissues since it regulates different cellular process such as proliferation, differentiation, and apoptosis and it can be a potential driver of resistance to a wide array of targeted therapies. In this study, we found that Notch-1 was significantly up-regulated in resistant tumor cells as well as HES1 and HEY. Additionally, inhibition of Notch-1 in resistant cells partially restored sensitivity to regorafenib treatment in vitro. Collectively, these data suggest a key role of Notch-1 in mediating the resistant effects of regorafenib in colorectal cancer cells, and also provide a rationale to improve the therapeutic efficacy of regorafenib.

Chronic myeloid leukemia (CML) is characterized by the accumulation of Philadelphia chromosome-positive (Ph+) myeloid cells. Ph+ cells occur via a reciprocal translocation between the long arms of chromosomes 9 and 22 resulting in constitutively active BCR-ABL fusion protein. Tyrosine kinase inhibitors (TKIs) are used against the kinase activity of BCR-ABL protein for the effective treatment of CML. However, the development of drug resistance, caused by different genetic mechanisms, is the major issue in the clinical application of TKIs. These mechanisms include changes in expression levels of microRNAs (miRNAs). miRNAs are short non-coding regulatory RNAs that control gene expression and play an important role in cancer development and progression. In the present review, we highlight the roles of miRNAs both in the progression and chemotherapy-resistance of CML. Our understanding of these mechanisms may lead to the use of this knowledge not only in the treatment of patients with CML, but also in other type of cancers.

At the end of 2019, a new disease recognized such as severe acute respiratory syndrome (SARS), was reported in Wuhan, China. This disease was caused by an unknown SARS coronavirus 2 (SARS-CoV-2); a virus is characterized by high infectivity among humans. In some cases, this disease can be asymptomatic, while in other cases can induce flu-like symptoms or acute respiratory distress syndrome, pneumonia and death. For this reason, the World Health Organization and Public Health Emergency of International Concern declared a pandemic status in January 2020. Currently, numerous countries have been involved in the development of effective vaccines to protect humans against SARS-CoV-2 infection. The present review will discuss the four vaccines, AZD1222 (AstraZeneca or Vaxzevria), Janssen (Ad26.COV2.S), Moderna/mRNA-1273 and BioNTech/Fosun/Pfizer BNT162b1, that are currently in use worldwide to understand their efficacy, but also evaluate the difficulties and challenges of vaccine development. Although several questions should be addressed regarding these vaccines, the current review will examine the viral elements used in the coronavirus-19 vaccine that can play a crucial role in inducing a strong immune response, as well as the different adverse effects that they can cause to individuals. Contents 1. The current history of COVID-19 2. Efficacy and adverse events of COVID-19 vaccines 3. Mass vaccination 4. Remaining questions regarding mRNA vaccines 5. Conclusions

Chronic Lymphocytic Leukemia (CLL) is the most common adult leukemia and is currently incurable. To expand the therapeutic armamentarium, we investigated antitumor activity of pyrrolo[1,2-b][1,2,5]benzothiadiazepine (PBTDs) in MEC1 cells. We found that PBTD (RS2778) treatment enhanced the activation of pro-apoptotic members, such as caspase-9, 3, poly (ADP-ribose) polymerase (PARP), and bax, but suppressed the activation of anti-apoptotic molecule BCL-2 in these cells. Furthermore, PBTD (RS2778)-induced autophagic cell death was verified by LC3-II conversion, and upregulation of Beclin-1 and ATG5. In addition, such compound impeded hyper phosphorylation of AKT as were determined by Western blot. In summary, PBTD (RS2778) inhibited viability and induced multiple cellular events including apoptosis, autophagic cell death, in human MEC1 cells. This distinct activity of PBTD (RS2778) against these cells suggests potential for PBTDs as a therapeutic agent for treatment of CLL.