Development Of Novel Antineoplastic Agents Research Articles

The impact of sodium-glucose cotransporter-2 inhibitors on the outcome of patients with colorectal adenocarcinoma.

3583 Background: The mortality of colorectal cancer remains high despite the development of novel anti-neoplastic agents. Preclinical studies have shown that colorectal cancer upregulates the expression of sodium-glucose cotransporter 2 (SGLT2) channels and inhibition of these channels by SGLT2 inhibitors (SGLT2i) reduces tumor proliferation. We aimed to investigate the impact of SGLT2i on the outcome of patients with colorectal cancer. Methods: We conducted a retrospective cohort study by including all adult patients with colorectal adenocarcinoma and type 2 diabetes mellitus in two tertiary centers in Taiwan. SGLT2i and non-SGLT2i patients were matched 1:1 based on age, sex, and cancer stage. The primary outcome was overall survival (OS) and progression-free survival (PFS), and the secondary outcomes were previously reported serious adverse events associated with the use of SGLT2i. Results: We identified 1347 patients with colorectal cancer and type 2 diabetes mellitus, from which 92 patients in the SGLT2i cohort were matched to the non-SGLT2i cohort. Compared to non-SGLT2i recipients, SGLT2i recipients had a higher rate of OS (5-year OS: 86.2% [95% CI: 72.0-93.5] vs. 62.3% [95% CI: 50.9-71.8], p = 0.013) and PFS (5-year PFS: 76.6% [95% CI: 60.7-86.7] vs. 57.0% [95% CI: 46.2-66.4], p = 0.021). In Cox proportional hazard analyses, the use of SGLT2i was associated with a 50-70% reduction in the risk of all-cause mortality and disease progression. The rate of cancer-associated mortality was lower in the SGLT2i group (7% vs. 21%, p = 0.005). SGLT2i were not associated with an increased risk of sepsis, hypoglycemia, or acute kidney injury. We did not detect any cases of urosepsis or diabetic ketoacidosis in the SGLT2i group. Conclusions: The use of SGLT2i was associated with a higher rate of survival in colorectal cancer patients with diabetes mellitus. [Table: see text]

Design, Synthesis and Antitumor Assessment of Phenylureas Bearing 5-Fluoroindolin-2-one Moiety.

The development of novel antineoplastic agents remains highly desirable. This study focuses on the design, synthesis, and antitumor evaluation of phenyl ureas bearing 5-fluoroindolin-2-one moiety. Three sets of phenylureas were designed and synthesized and their antiproliferative ability was measured against four human carcinoma cell lines (Hela, Eca-109, A549, and MCF-7) via MTT assay. In vivo anticancer activity was further evaluated in xenograft models of human breast cancer (MCF-7). A total of twenty-one new compounds were synthesized and characterized by means of 1H and 13C NMR as well as HR-MS. Three sets of compounds (1a‒1c, 2a‒2c, and 3a‒3c) were initially constructed, and preliminary antiproliferative activities of these molecules were evaluated against Hela, Eca-109, A549 and MCF-7, highlighting the meta-substituted phenylureas (1a‒1c) as the most cytotoxic set. A series of meta-substituted phenylureas derivatives (1d‒1o) were then designed and synthesized for structure-activity relationship study. Most of the new compounds showed desirable cytotoxicity, among which compound 1g exhibited the most remarkable cytotoxic effects against the tested human cancer cells with IC50 values ranging from 1.47 to 6.79 μM. Further studies showed that compound 1g suppressed tumor growth in human breast cancer (MCF- 7) xenograft models without affecting the body weight of its recipients. In this study, twenty-one new compounds, containing the privileged structures of phenylurea and 5-fluoroindolin-2-one, were designed and synthesized. Subsequent structureactivity studies showed that 1g was the most bioactive antitumor agent among all tested compounds, hence a potentially promising lead compound once given further optimization.

Synthesis and cytotoxicity evaluation of N-(5-Mercapto-4H-1,2,4-triazol-3-yl)-2-phenylacetamide derivatives as apoptosis inducers with potential anticancer effects

Background: Discovery of new anticancer drugs is one of the urgent issues in the medicinal chemistry researches. Incidence of severe side effects and acquired resistance to the current medications are the logical reasons for the development of novel antineoplastic agents. Methods: Herein, a new series of 4H-1,2,4-triazole derivatives was synthesized and subsequently their cytotoxicity was assessed using dimethylthiazol diphenyltetrazolium bromide assay. Furthermore, activity of caspase 3, mitochondrial membrane potential (MMP), and generation of reactive oxygen species (ROS) were investigated. All synthesized derivatives (3a–3o) were tested against Hela (cervical cancer), A549 (lung carcinoma), and U87 (glioblastoma), and the obtained data were compared with doxorubicin. Results: Among the chlorinated derivatives, compound 3c with para positioning of the chlorine on the phenyl residue possessed higher cytotoxicity (IC50 = s3.2 ± 0.6 μM) than compounds 3a and 3b, which positioned chlorine at ortho and meta position, respectively. Chlorine as electron-withdrawing moiety caused enhancement in cytotoxicity. Conclusion: Fortunately, most of the tested compounds showed remarkable cytotoxic activity toward applied cells, especially Hela. Activation of caspase 3, MMP reduction, and ROS generation were also observed for the studied compounds.

Rational Drug Design of Antineoplastic Agents Using 3D-QSAR, Cheminformatic, and Virtual Screening Approaches.

Computer-Aided Drug Design has strongly accelerated the development of novel antineoplastic agents by helping in the hit identification, optimization, and evaluation. Computational approaches such as cheminformatic search, virtual screening, pharmacophore modeling, molecular docking and dynamics have been developed and applied to explain the activity of bioactive molecules, design novel agents, increase the success rate of drug research, and decrease the total costs of drug discovery. Similarity, searches and virtual screening are used to identify molecules with an increased probability to interact with drug targets of interest, while the other computational approaches are applied for the design and evaluation of molecules with enhanced activity and improved safety profile. In this review are described the main in silico techniques used in rational drug design of antineoplastic agents and presented optimal combinations of computational methods for design of more efficient antineoplastic drugs.

Hippuristanol - A potent steroid inhibitor of eukaryotic initiation factor 4A.

Protein synthesis and its regulatory signaling pathways play essential roles in the initiation and maintenance of the cancer phenotype. Insight obtained over the last 3 decades on the mechanisms regulating translation in normal and transformed cells have revealed that perturbed control in cancer cells may offer an Achilles' heel for the development of novel anti-neoplastic agents. Several small molecule inhibitors have been identified and characterized that target translation initiation - more specifically, the rate-limiting step where ribosomes are recruited to mRNA templates. Among these, hippuristanol, a polyhydroxysteroid from the gorgonian Isis hippuris has been found to inhibit translation initiation by blocking the activity of eukaryotic initiation factor (eIF) 4A, an essential RNA helicase involved in this process. Herein, we highlight the biological properties of this compound, its potential development as an anti-cancer agent, and its use to validate eIF4A as an anti-neoplastic target.

The Effect of Arvanil on Prostate Cancer Cells Studied by Whole Cell High Resolution Magic Angle Spinning NMR

The transient receptor potential cation channel subfamily V member 1 (TRPV1) has recently gained attention as a potential target for the development of novel antineoplastic agents. It has been reported that the TRPV1 agonist arvanil has effective antiproliferative effects in studies using human breast cancer cells lines. In an extension of this research we have evaluated the IC50 values of arvanil in the prostate cancer cell lines PPC-1 (primary) and TSU (metastatic). Both TSU and PPC-1 cell lines are sensitive to treatment with arvanil. This result prompted our investigations into the changes in “cell metabolism” associated with prostate cancer progression and the effect of arvanil treatment. To this end, we have employed High Resolution Magic-Angle Spinning (HR-MAS) NMR spectroscopy on whole cells to determine the differences in the relative amount of cell metabolites and changes in small molecule metabolism following treatment of the TSU and PPC-1 cells with arvanil. We evaluated and confirmed that the existing “biomarkers” such as elevated tCho and decreased citrate in prostate cancer are well correlated with prostate cancer progression. In addition, metastatic TSU cells also contain elevated level of lactate and glutamine, and contain much less creatine. Upon treatment with arvanil, a number of biomolecules were found to undergo changes in intracellular levels during apoptosis. These data will potentially permit the further characterization of signaling pathways associated with TRPV1 activation as well as identifying new targets for the development of novel antineoplastic agents.

25-Methoxylprotopanaxadiol derivatives and their anti-proliferative activities

(20R)-25-Methoxyl-dammarane-3β,12β,20-triol (25-OCH3-PPD) is a dammarane-type sapogenin showing anti-proliferative potential. In our study, two series of analogs substituted at the C-3 or C-3 and C-12 positions with fatty acids were prepared conveniently. The cytotoxic activity of these compounds was evaluated using four different human tumor cell lines (A549, Hela, HT-29 and MCF-7) and a normal cell line (IOSE144). As compared with 25-OCH3-PPD, compounds 1a, 1b, 2a and 2b showed better anti-proliferative activities against all tumor cell lines and all the derivatives, with low toxicities in the normal cell line. Compound 1a (C-3 monoformiate) exhibited the strongest activity with the IC50 value of 5.2μM towards HT29 cells. The results indicated that the difference in the substituents may affect the anti-proliferative activity of the compounds. The longer the side chain of 25-OCH3-PPD is, the lower the anti-proliferative activity would be. This information may be useful for evaluating the structure–activity relationship of other dammarane-type sapogenins and for development of novel antineoplastic agents.

Of Mice and (Wo)Men: Is This Any Way to Test a New Drug?

Of Mice and (Wo)Men: Is This Any Way to Test a New Drug?

Role of the retinoblastoma protein in the pathogenesis of human cancer.

The retinoblastoma gene (RB-1) was originally identified as the gene involved in hereditary retinoblastoma. However, RB-1 mutations are found in a number of common mesenchymal and epithelial malignancies. The retinoblastoma protein (pRB) acts as a transcriptional regulator of genes involved in DNA synthesis and cell-cycle control. In this regard, the functional interaction between pRB and the E2F transcription factor family appears to be critical. The pRB-E2F interaction is, in turn, regulated by a pathway that includes cyclin D1, cdk4, and p16. Mutations that affect this pathway have been documented in nearly every type of adult cancer. Thus, perturbation of pRB function may be required for the development of cancer. Insights into the biochemical functions of pRB, and its upstream regulators, may form the basis for the development of novel antineoplastic agents.