Current Cancer Drug Targets - Volume 20, Issue 5, 2020

CDK9 is an important cell-cycle control enzyme essential in transcription, elongation, and mRNA maturation. Overexpression of CDK9 has been reported in several diseases, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, and malignant melanoma. Recent research revealed that CDK9-inhibitors have a major impact on the induction of apoptosis in hepatocellular carcinoma (HCC) cell lines. Despite surprisingly promising results in in vitro and in vivo research, no CDK9 related therapy is currently allowed in cases of HCC. Furthermore, due to their high specificity, the inhibitors had no effects on unaltered hepatocytes and no toxic effects were shown. Considering that they were well tolerated and showed relatively few severe side-effects in mice, CDK9- inhibitors would seem to be promising targets in HCC biomarker-guided immunotherapy. Studies have verified that CDK9 has a pivotal role in c-Myc-mediated tumor growth and CDK9 inhibitors inhibit not only its progression but diametrically decrease both the mass and size of HCC nodules. CDK9-inhibitors seem to be a promising target in HCC treatment.

Cancer is still a serious public issue that humans face. Chemoresistance is one of the most important reasons for relapse and poor prognosis. The accumulated data support that the polymorphisms in IGF1 are correlated with both circulating IGF1 levels and cancer risk and activation of IGF1signaling enhances the progression of cancer. Here, we emphasize the role of IGF1 in resistance to various chemotherapies. Dysregulation of IGF1-related lncRNAs may also play an important role in the regulation of chemoresistance by IGF1. Finally, targeting the IGF1 pathway and lncRNAs is effective for increasing the sensitivity of cancer cells to chemotherapies. More basic and clinical studies need to be conducted to investigate the value of targeting IGF1 and IGF1-related lncRNAs in restoring sensitivity to chemotherapies.

Background: Complex central nervous system (CNS) is made up of neuronal cells and glial cells. Cells of central nervous system are able to regenerate after injury and during repairing. Sonic hedgehog pathway initiated by Shh-N a glycoprotein plays vital role in CNS patterning growth, development and now tumorigenesis. Nkx2.2 homeodomain transcription factor is an effecter molecule, which is positively regulated by Shh during normal growth. Nkx2.2 is essential for V3 domain specification during neural tube patterning at embryonic stage. MBP + oligodendrocytes are differentiated from progenitor cells which express Olig2. Nx2.2 is co-expressed with Olig2 in oligodendrocytes and is essential for later stage of oligodendrocyte maturation. Objective: This review paper explores the potential role of Nkx2.2 transcription factor in glioblastoma development. Conclusion: Shh pathway plays a vital role in oligodendrocytes differentiation and Nkx2.2 transcription factor is essential for oligodendrocytes differentiation and maturation. Intriguingly, down regulation of Nkx2.2 transcription factor with aberrant Shh signaling pathway is reported in glioma samples. So here it is suggested that Nkx2.2 expression pattern could be used as a potential biomarker for the early diagnosis of glioma.

Idronoxil has been the subject of more than 50 peer-reviewed publications over the last two decades. This isoflavone is an intriguing regulator of multiple signal transduction pathways, capable of causing a range of biological effects, including cell cycle arrest, apoptosis, an ability to stimulate the immune system, and inhibition of angiogenesis. These multifaceted actions suggest that idronoxil has the potential to synergize with, or complement, a wide range of cancer therapies. Whilst clinically tested in the past, idronoxil’s journey was discontinued as a result of its low bioavailability in humans when administered either intravenously or orally, though strategies to overcome this issue are currently being explored. Here, we summarize the current literature regarding the key cellular targets of idronoxil and the mechanisms by which idronoxil exerts its anticancer effects, laying a new foundation toward giving this unique molecule a second chance of contributing to the future of cancer treatment.

Background: Chemokine 13 (CXCL13) and its chemokine receptor 5 (CXCR5) are involved in the onset of various types of cancer. However, their role in cervical cancer (CC) remains unknown. Objective: To investigate the role of chemokine 13 (CXCL13) and its receptor in CC. Methods: The expression of CXCL13/CXCR5 and the infiltration of CXCR5+CD8+ T cells in CC, cervical intraepithelial neoplasia (CIN), normal cervical epithelial (NCE) tissues, and in CC cell lines were analysed and the associated clinical significance was determined. In vitro, CXCL13 overexpression and DNA methyltransferase inhibition (through S110) were used to investigate the biological function and the underlying mechanism that regulates CXCL13 expression. Tumor growth and liver metastasis were also evaluated in the xenogenous subcutaneously implant model. Results: CXCL13/CXCR5 expression levels and the infiltration of CXCR5+CD8+ T cells were significantly decreased in CC tissues compared with CIN and NCE tissues. CXCL13 downregulation was significantly correlated with the FIGO stages, lymph node metastasis, interstitial infiltration depth, and pathological grade. The overexpression of CXCL13 suppressed CC cell migration. CXCL13 downregulation was associated with hypermethylation in CC cell lines, and primary tumor biopsies. Furthermore, a CpG dinucleotide at the HIF-1a transcription factor motifs in the promoter element of CXCL13 was consistently methylated in CC cells and associated with HIF-1a. CXCL13 overexpression and S110 treatment dramatically repressed tumor growth and liver metastasis in the xenograft model; whereas it’s low expression increased the risk of death in CC patients. Conclusion: DNA methylation-dependent CXCL13 downregulation may promote cervical carcinogenesis and progression.

Aims: Characterization of a small anticancer compound. Background: The development of small molecules as new anti-cancer therapeutics is necessary to improve anti-tumor efficacy and reduce toxicities, especially for the treatment of brain tumors, where only small molecules can effectively cross the brain-blood barrier. Several novel hits were previously selected by concurrently screening colon and glioma cancer cell lines with a sensorconjugated reporter system. Here, we focused on one of them. Objective: Elucidating the potential target(s) of a novel anticancer compound. Methods: Computer-assisted structural and motif analysis (least absolute shrinkage and selection operator or LASSO score) was used to assess compound’s targets, then direct kinase activity assays were used for the confirmation; Western blot of phosphorylated kinases, as well as FACS and caspase 3/7 activity assays, were used to decipher the action mechanisms. Finally, the expression profiling of proteins involved in various G-protein pathways by real-time PCR was performed. Results: The small chemical, (4E)-4-[2-(9-ethyl-9H-carbazol-3-yl)hydrazin-1-ylidene]-3-methyl- 4,5-dihydro-1H-pyrazol-5-one, with a formula C18H17N5O and MW of 319.36, designated as VUGX01, was predicted to be a ligand/inhibitor to receptor tyrosine kinases (RTKs) by computer analysis (least absolute shrinkage and selection operator or LASSO score). However, direct analysis with recombinant kinases showed that it is not an effective inhibitor to the popular receptor kinases at 1μM concentration. This compound can activate caspases in some tumor cell lines but has minimal effects on the cell cycle. Drug treatments lead to the changes in phosphorylation of AKT and c- RAF, as well as the expression level of MAP2K, suggesting this compound may interact with Gprotein coupled receptors (GPCRs). The expression profiling of 82 proteins involved in various Gprotein pathways by real-time PCR showed that the treatment up-regulates the expression of several proteins, including angiotensinogen, angiotensin II receptor, and IP3-kinase catalytic subunit gamma. Conclusion: VUGX01 can effectively block proliferation and induce apoptosis of certain types of cancer cells, even it is predicted by high LASSO score, but it is not an effective RTKs inhibitor, it may inhibit cell growth through acting as a novel ligand to one or several GPCRs.

Background: Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) play key roles in the antiviral response, but recent works show that RLR activation elicits anticancer activity as well, including apoptosis. Previously, we demonstrated that the anticancer activity of the RLR agonist Poly(I:C)-HMW/LyoVec™ [Poly(I:C)-HMW] against human lung cancer cells was enhanced by cotreatment with ionizing radiation (IR). In addition, cotreatment with Poly(I:C)-HMW and IR induced apoptosis in a Fas-independent manner, and increased Fas expression on the cell surface. Objective: The current study investigated the resultant hypothesis that Fas ligand (FasL) may enhance apoptosis in lung cancer cells cotreated with Poly(I:C)-HMW+IR. Methods: FasL was added into culture medium at 24 h following cotreatment with Poly(I:C)- HMW+IR, after upregulation of cell surface Fas expression on human lung cancer cells A549 and H1299 have already been discussed. Results: FasL enhanced the apoptosis of A549 and H1299 cells treated with Poly(I:C)-HMW+IR. Similarly, IR alone - and not Poly(I:C)-HMW - resulted in the upregulation of cell surface Fas expression followed by a high response to FasL-induced apoptosis, thus suggesting that the high sensitivity of cells treated with Poly(I:C)-HMW+IR to FasL-induced apoptosis resulted from the cellular response to IR. Finally, knockdown of Fas by siRNA confirmed that the high response of treated cells to FasL-induced apoptosis is dependent on Fas expression. Conclusion: In summary, the present study indicates that upregulated Fas expression following cotreatment with Poly(I:C)-HMW and IR is responsive to FasL-induced apoptosis, and a combination of RLR agonist, IR, and FasL could be a potential promising cancer therapy.

Background and Aims: Hepatocellular carcinoma (HCC) is a highly aggressive cancer with few treatment options. Toll-like receptor 3 (TLR3) plays a key role in innate immunity and may affect the development of cancers. This study aimed to investigate the association between TLR3 gene polymorphism and HCV-related hepatocellular carcinoma in Egypt. Methods: This work was conducted on 70 individuals; fifty HCV cirrhotic patients were included in two groups; with HCC (30 patients) and without HCC (20 patients) compared with a group of 20 apparently healthy controls. All of the studied individuals underwent clinical-laboratory evaluation. TLR3 gene single-nucleotide polymorphism (SNP) (+1234C/T) was tested by polymerase chain reaction- restriction fragment length polymorphism. Results: This study reported that the prevalence of TLR3 +1234TT genotype was significantly increased in cirrhotic patients with HCC than without HCC, while it was not detected at all among the controls. When analyzing the TLR3 SNP +1234C/T with different clinical parameters in HCC patients, there was a significant association between+1234C/T SNP; namely TT genotype and each of the hepatic focal lesions' number, size and the patients' higher Okuda and BCLC stages. No association could be detected between TLR3 SNP and the age, sex, Child-Pugh grades, MELD score or AFP of the studied HCC cases. Conclusion: TLR3 gene SN P +1234C/T could be a novel risk factor for the HCV-related HCC among the Egyptian population.