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Matrine, a sophora alkaloid, has been demonstrated to exert antitumor effects on many types of cancer. However, its bioactivity is weak and its potential druggability is low. We modified the structure of matrine and obtained a new matrine derivative, WM130 (C 30 N 4 H 40 SO 5 F), which exhibited better pharmacological activities than matrine. In this study, we investigated the antitumor activity and the underlying mechanisms of WM130 on hepatocellular carcinoma (HCC) cells in vitro and in vivo , and found that WM130 inhibited the proliferation, invasion, migration and induced apoptosis of HCC cells in a dose-dependent manner. Furthermore, after treatment with WM130, the expressions of p-EGFR, p-ERK, p-AKT, MMP-2 and the ratio of Bcl-2/Bax were significantly down-regulated, whereas the expression of PTEN was increased in HCC cells. Moreover, WM130 inhibited Huh-7 xenograft tumor growth in a dose-dependent manner after intravenous administration. Immunohistochemistry results demonstrated that WM130 treatment resulted in down-regulation of p-EGFR, MMP-2, and Ki67 and up-regulation of PTEN. The findings indicated that WM130 could inhibit cell proliferation, invasion, migration and induced apoptosis in HCC cells by suppressing EGFR/ERK/MMP-2 and PTEN/AKT signaling pathways and may be a novel effective candidate for HCC treatment. [ABSTRACT FROM AUTHOR]

Abstract: Malignant melanoma is one of the most lethal and aggressive human malignancies. It is notoriously resistant to all of the current therapeutic modalities, including chemotherapy. Suppressed apoptosis and extraordinary invasiveness are the distinctive features that contribute to the malignancy of melanoma. Dacarbazine (DTIC) has been considered as the gold standard for melanoma treatment with a response rate of 15–20%. Unfortunately, the resistance to this chemotherapeutic agent occurs frequently. ZD55-IL-24 is a selective conditionally replicating adenovirus that can mediate the expression of interleukin-24 (IL-24) gene, which has a strong anti-tumor effect. In this study, we hypothesized that a combination of ZD55-IL-24-mediated gene virotherapy and chemotherapy using DTIC would produce an increased cytotoxicity against human melanoma cells in comparison with these agents alone. Our results showed that the combination of ZD55-IL-24 and DTIC significantly enhanced the anti-tumor activity by more effectively inducing apoptosis in melanoma cells than either agent used alone without any overlapping toxicity against normal cells. This additive or synergistic effect of ZD55-IL-24 in combination with DTIC in killing human malignant melanoma cells implies a promising novel approach for melanoma therapy. [Copyright &y& Elsevier]

Ethnopharmacological relevance: Lysimachia clethroides Duby is a traditional Chinese medicinal herb has been used in China to treat edema, jaundice diseases, hepatitis, tumor and inflammations, but the anti-tumor mechanisms are unclear. Aim of the study: The present study was undertaken to investigate if total flavonoids from Lysimachia clethroides Duby (ZE4) possesses anti-cancer effects through apoptotic pathways in human chronic myeloid leukemia K562 cells. Materials and methods: K562 cells were treated with different concentrations of ZE4 at different time intervals. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell apoptosis was assessed by flow cytometry, Hoechst 33258 staining and COMET assay. Western blot analysis was used to detect Bcl-2, Trail and DR5 expressions. Results: 15 flavonoids were isolated and identified from ZE4. ZE4 could inhibit the growth of K562 cells significantly by induction of apoptosis. Marked morphological changes of apoptosis, DNA fragmentation and single DNA strand breakages were observed clearly after treatment of ZE4. Bcl-2 expression was down-regulated remarkably while Fas, Trail and DR5 up-regulated when apoptosis occurred. Conclusions: This result suggests that total flavonoids of Lysimachia clethroides Duby exert potential anti-cancer activity through growth inhibition and apoptosis in K562 cells. [Copyright &y& Elsevier]

[Display omitted] • 41 novel FAK covalent inhibitors were synthesized. • Compound 11w displayed highest inhibition of FAK and tumor cells. • 11w inhibited the clone formation and migration of tumor cells, inducing apoptosis. • 11w covalently inhibited the autophosphorylation of FAK in a dose-dependent manner. • 11w showed adequate oral bioavailability and significant antitumor efficacy in vivo. Forty-one new focal adhesion kinase (FAK) covalent inhibitors were designed and synthesized based on FAK inhibitor TAE226. Compound 11w displayed the highest inhibition of FAK with an IC 50 value of 35 nM and exhibited potent anticancer activity against Hela, HCT116 and MDA-MB-231 cell lines with IC 50 values of 0.41, 0.01 and 0.11 μM respectively, compared to TAE226 (2.68, 0.64 and 4.19 μM respectively). 11w also inhibited the clone formation and migration of HCT-116 cells and stimulated cell cycle arrest in the G 2 /M phase, inducing tumor cell apoptosis. Compound 11w formed a covalent bond with the Cys427 residue of FAK in a docking model, inhibiting the autophosphorylation of FAK and downstream proteins in a dose-dependent manner. Moreover, 11w showed adequate oral bioavailability of 21.02%. A 74.20% inhibition of tumor growth in the HCT116 xenograft model was also observed. These data indicate that 11w is a promising covalent inhibitor of FAK. [ABSTRACT FROM AUTHOR]

Mcl-1 is an anti-apoptotic member of Bcl-2 family proteins. The development of inhibitors of Mcl-1 has been challenging. To develop metal-based Mcl-1inhibitors, twenty two copper(II) complexes 25 – 46 with 9-substituted β-carboline derivatives were reported. Complexes 38 and 39 showed higher cytotoxicity than the corresponding ligands or cisplatin. The most potent complex 39 presented higher selectivity to Mcl-1 than other Bcl-2 family proteins, and killed cancer cells via Bax/Bak mediated apoptosis. Complex 39 showed an excellent safety profile in mouse model, and significantly inhibited the tumor growth in NCI-H460 tumor bearing model, which is more potent than AZD5991 at the same dosage. Complex 39 prolonged the survival time of the tumor bearing mice. Complex 39 is the first metal-based Mcl-1 inhibitor acting as a potential anticancer agent. Image 1 • Complex 39 is a novel metal-based Mcl-1 inhibitor with strong antitumor activity. • Complex 39 induced Bax/Bak mediated apoptosis. • Complex 39 significantly inhibited tumor growth in mouse xenograft model. • Complex 39 increased the survival time in mouse xenograft model. • Complex 39 showed a good safety margin in mice. [ABSTRACT FROM AUTHOR]

The root of Croton crassifolius has been used as a traditional Chinese medicine (TCM), called Radix Croton Crassifolius, and commonly known as "Ji Gu Xiang" in Chinese. Its medicinal value has been recorded in several medical books or handbooks, such as "Sheng Cao Yao Xing Bei Yao", "Ben Cao Qiu Yuan" and "Zhong Hua Ben Cao". It has been traditional employed for treating sore throat, stomach-ache, rheumatism and cancer. At present, there are limited studies on the evaluation of low-polarity extracts of roots in C. crassifolius. Consequently, the aim of this study was to evaluate the antitumor effect of the low-polarity extract of C. crassifolius root. Extracts were obtained by supercritical fluid extraction. The extracts were tested for antitumor effects in vitro on several cancer cell lines. A CCK-8 kit was used for further analysis of cell viability. A flow cytometer and propidium iodide staining were used to evaluate the cell cycle and apoptosis. Hoechst staining, JC-1 staining and the fluorescence probe DCFH-DA were used to evaluate apoptotic cells. Molecular mechanisms of action were analyzed by quantitative RT‒PCR and Western blotting. Immunohistochemistry was used for the evaluation of xenograft tumors in male BALB/c mice. Finally, molecular docking was employed to predict the bond between the desired bioactive compound and molecular targets. Eleven diterpenoids were isolated from low-polarity C. crassifolius root extracts. Among the compounds, chettaphanin II showed the strongest activity (IC 50 = 8.58 μM) against A549 cells. Evaluation of cell viability and the cell cycle showed that Chettaphanin II reduced A549 cell proliferation and induced G2/M-phase arrest. Chttaphanin II significantly induced apoptosis in A549 cells, which was related to the level of apoptosis-related proteins. The growth of tumor tissue was significantly inhibited by chettaphanin II in experiments performed on naked mice. The antitumor mechanism of chettaphanin II is that it can obstruct the mTOR/PI3K/Akt signaling pathway in A549 cells. Molecular docking established that chettaphanin II could bind to the active sites of Bcl-2 and Bax. Taken together, the natural diterpenoid chettaphanin II was identified as the major antitumor active component, and its potential for developing anticancer therapies was demonstrated for the first time by antiproliferation evaluation in vitro and in vivo. [Display omitted] • Eleven diterpenoids were obtained from the SFE extract of C. crassifolius roots. • Chettaphanin II showed the strongest antitumor activity against A549 cells. • Chettaphanin II inhibited A549 cell proliferation and arrested cells in G2/M-phase. • Chettaphanin II induced A549 cell apoptosis by inhibiting PI3K/AKT/mTOR pathway. • Chettaphanin II significantly inhibited the growth of tumor tissue in nude mice. [ABSTRACT FROM AUTHOR]

Abstract: Six new platinum(II) complexes with mono-aminophosphonate ester were synthesized and characterized by elemental analysis, 1H NMR, ESI-MS as well as single crystal X-ray diffraction analysis. They are mononuclear structures. In all the crystal structures of complexes 1–6, the platinum centre adopts an approximately square-planar geometry, which were found to possess excellent solubility in both organic solvents and water and exhibit considerable cytotoxicity against MG-63, SK-OV-3 and HepG2 cell lines, but low cytotoxicity towards normal human liver cell HL-7702. In contrast to cisplatin, their antitumour activities are achieved through the induction of cell apoptosis by G1 cell-cycle arrest. [Copyright &y& Elsevier]

Abstract In this work, we designed and synthesized tacrine platinum(II) complexes [PtClL(DMSO)]⋅CH 3 OH (Pt1), [PtClL(DMP)] (Pt2), [PtClL(DPPTH)] (Pt3), [PtClL(PTH)] (Pt4), [PtClL(PIPTH)] (Pt5), [PtClL(PM)] (Pt6) and [PtClL(en)] (Pt7) with 4,4′-dimethyl-2,2′-bipyridine (DMP), 4,7-diphenyl-1,10-phenanthroline (DPPTH), 1,10-phenanthroline (PTH), 2-(1-pyrenecarboxaldehyde) imidazo [4,5-f]-[1,10] phenanthroline (PIPTH), 2-picolylamine (PM) and 1,2-ethylenediamine (en) as telomerase inhibitors and p53 activators. Biological evaluations demonstrated that Pt1 Pt7 exhibited cytotoxic activity against the tested NCI H460, Hep-G2, SK-OV-3, SK-OV-3/DDP and MGC80-3 cancer cell lines, with Pt5 displaying the highest cytotoxicity. Pt5 exhibited an IC 50 value of 0.13 ± 0.16 μM against SK-OV-3/DDP cancer cells and significantly reduced tumor growth in a Hep-G2 xenograft mouse model (tumor growth inhibition (TGI) = 40.8%, p < 0.05) at a dose of 15.0 mg/kg. Interestingly, Pt1 Pt7 displayed low cytotoxicity against normal HL-7702 cells. Mechanistic studies revealed that these compounds caused cell cycle arrest at the G2/M and S phases, and regulated the expression of CDK2, cyclin A, p21, p53 and p27. Further mechanistic studies showed that Pt5 induced SK-OV3/DDP cell apoptosis via dysfunction of mitochondria, inhibition of the telomerase activity by directly targeting the c-myc promoter, and activation of the p53 signaling pathway. Taken together, Pt5 has the potential to be further developed as a new antitumor drug. Graphical abstract Pt5 induced SK-OV-3/DDP cell apoptosis via dysfunction of mitochondria, inhibition of the telomerase activity and activation of the p53 signaling pathway. Image 1 Highlights • We designed and synthesized tacrine platinum(II) complexes Pt1 Pt7 as telomerase inhibitors and p53 activators. • Pt5 display high in vivo and in vitro anticancer activity. • Pt5 may trigger cell apoptosis via a mitochondrial dysfunction pathway. [ABSTRACT FROM AUTHOR]

There iridium(III) complexes, [Ir(3-MeO-Phtpy)Cl 3 ] ( 1 ), [Ir(2-MeO-Phtpy)Cl 3 ] ( 2 ) and [Ir(4-MeO-Phtpy)Cl 3 ] ( 3 ) with 4′-(3-methoxyphenyl)-2,2′:6′,2″-terpyridine (3-MeO-Phtpy), 4′-(2-methoxyphenyl)-2,2′:6′,2″-terpyridine (2-MeO-Phtpy) and 4′-(4-methoxyphenyl)-2,2′:6′,2″-terpyridine (4-MeO-Phtpy) as ligands, respectively, were synthesized and evaluated for their antiproliferative activities. In these complexes, the iridium(III) center adopts a six-coordinate distorted octahedral geometry. Among them, complex 1 exhibited the most potent activity, with IC 50 values of 3.19–27.77 μ M against four cancer cell lines (BEL-7404, Hep-G2, NCI-H460 and MGC80-3 cells). Cellular mechanism studies suggested that complexes 1 – 3 directly targeted c-myc promoter elements and inhibited the telomerase activity. In addition, complexes 1 – 3 may trigger cell apoptosis via a mitochondrial dysfunction pathway. We postulated that the difference in the in vitro antitumor activities of complexes 1 – 3 is mainly dependent on the position of the methoxy group on the phenyl ring of the iridium ligand. [ABSTRACT FROM AUTHOR]

Two G-quadruplex ligands: [Co( H-L a ) 2 Cl 2 ] ( Co1 ) and [Co( L b ) 2 ][CoCl 4 ]⋅2H 2 O ( Co2 ) have been synthesized and characterized. Two cobalt oxoisoaporphine complexes exhibited selective cytotoxicity to SK-OV-3/DDP cells than for HL-7702 cells. Cytotoxic mechanism studies indicated that both Co1 and Co2 were telomerase inhibitor targeting c-myc, telomere, and bcl-2 G4s, and triggering cell senescence and apoptosis, which caused S phase arrest. They also induced mitochondrial dysfunction. The better antitumor activity of Co2 , which should be correlated with a moiety of 2-[5-(2-pyridinyl)-1 H -pyrrol-2-yl]pyridine in the L b . Importantly, Co2 at high doses showed at least the same level of tumor growth inhibition efficacy compared to that of cisplatin, and better in vivo safety profile. [ABSTRACT FROM AUTHOR]

Novel approaches to pre-transplant conditioning are needed to improve treatment of advanced T-cell malignancies. We investigated the synergism of fludarabine (Flu), clofarabine (Clo), busulfan (Bu), and romidepsin (Rom) in T-cell lines and patient-derived cell samples. [Flu + Clo + Bu + Rom] had combination indexes of 0.4–0.5 at ∼50% cytotoxicity in PEER and SUPT1 cells, suggesting synergism. Drug exposure resulted in histone modifications, DNA-damage response (DDR), increased reactive oxygen species (ROS), decreased glutathione (GSH) and mitochondrial membrane (MM) potential, and apoptosis. Similar activation of DDR and apoptosis was observed in patient samples. The PI3K-AKT-mTOR, NFκB, Raf-MEK-ERK, JAK-STAT and Wnt/β-catenin pro-survival pathways were inhibited by the 4-drug combination. The SAPK/JNK stress pathway was activated. A novel finding was the down-regulation of the drug transporter MRP1. We propose the following mechanisms of synergism: Flu, Clo and Rom induce histone modifications and chromatin remodeling, exposing DNA to Bu alkylation; the increased production of ROS, due to drug-mediated stress response and decreased GSH, damages the MM causing leakage of pro-apoptotic factors; down-regulation of MRP1 increases intracellular Bu concentration and exacerbates the DDR; and inhibition of multiple survival pathways. Our results provide the basis for a clinical trial to evaluate [Flu + Clo + Bu + Rom] as part of conditioning regimen for refractory T-cell malignancy patients undergoing stem cell transplantation. [ABSTRACT FROM AUTHOR]

[Pt(Q) 2 ] ( 1 ) and [Pt(MQ) 2 ] ( 2 ) exhibited enhanced cytotoxicity against BEL-7404, Hep-G2, NCI–H460, T-24, A549 tumor cells but low cytotoxicity on normal HL-7702 cells. 1 and 2 could cause the cell cycle arrest in G2 and S phase, respectively. While pifithrin-α, a specific p53 inhibitor, induced cell cycle arrest in G1 phase. Although 1 , 2 and pifithrin-α caused serious inhibition on p53, 1 and 2 significantly cause the loss of mitochondrial membrane potential and increase of the reactive oxygen species level, cytochrome c , apaf-1 and caspase-3/9 ratio in BEL-7404 cells. 1 and 2 may trigger the cell apoptosis through a mitochondrial dysfunction pathway whereas pifithrin-α does not. The interactions of 1 and 2 with DNA are most probably via an intercalation. [ABSTRACT FROM AUTHOR]

A new platinum(II) complex of [Pt II (L) (pn)]Cl·2H 2 O ( 1 ) (pn = 1,3-propanediamine) with 2-(4-methoxy-phenyl)imidazo [4,5-f]-[1,10]phenanthrolin (H-L) was synthesized and characterized. In complex 1 , the platinum adopts a four-coordinated square planar geometry. Complex 1 exhibited selective cytotoxicity against NCI–H460, BEL-7402, SK-OV-3, SK-OV-3/DDP and HeLa cell lines with IC 50 values in the micromolar range (9.7–35.8 μM), but low cytotoxicity toward normal human liver HL-7702 cells. Complex 1 caused HeLa cell cycle arrest at S phase and it induced HeLa apoptosis by the activation of caspase-3/9. Various experiments showed that complex 1 preferred to bind with G-quadruplex in c-myc. Taken together, we found that complex 1 exerted its antitumor activity mainly via inhibiting telomerase by interaction with c-myc quadruplex and activation of caspase-3/9. [ABSTRACT FROM AUTHOR]

Abstract: Three mononuclear silver(I) complexes with 8-hydroxyquinoline, 8-hydroxy-2-methylquinoline and 5-chloro-8-quinolinol were synthesized and characterized by elemental analysis, NMR, ESI-MS as well as single crystal X-ray diffraction analysis. All the structures of complexes 1–3 with the silver center adopting an approximately four-coordinated distorted tetragonal pyramid geometry were found to exhibit selective cytotoxicity against HepG2, NCI-H460, BEL-7404 and HeLa cell lines with IC50 values generally in the micromolar range (1.7–14.6μM), but low cytotoxicity towards normal human liver cell HL-7702. A combination of flow cytometric analysis and molecular probe observation indicated that complexes 1–3 could induce HepG2 cell apoptosis. Molecular mechanism studies suggested that complexes 1–3-induced apoptosis is mediated through the intrinsic apoptotic pathway with changes in mitochondrial membrane potential by finally activating effector caspase-3/9 to trigger cell apoptosis. Further studies revealed that complexes 1 and 2 caused cell cycle arrest at S phase, while complex 3 induced G1 cell cycle arrest in HepG2 cells. Taken together, these results suggest that complexes 1–3 may be potential candidates for cancer therapy. [Copyright &y& Elsevier]