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Objective: To evaluate the efficacy and safty of China-made flumatinib mesylate in the treatment of chronic myeloid leukemia in chronic phase (CML-CP)., Methods: 42 CML-CP patients treated with Chinese produced flumatinib (oral, 600 mg, 1/d) were included in the study, including 14 newly diagnosed patients and 28 patients underwent conversion therapy. The hematological, cytogenetic and molecular response and safety were observed and evaluated after 3, 6 and 12 months of treatment., Results: 35 patients were treated for more than 3 months, among which 31 patients were treated for more than 6 months and 17 patients were treated for more than 12 months. After 3 months of treatment, 33 patients underwent hematological, cytogenetic and molecular examination. Of these, 32 patients achieved complete hematological response (CHR), 13 patients achieved complete cytogenetic response (CCyR), 20 patients showed BCR-ABL IS ≤10% and 7 patients reached major molecular response (MMR). After 6 months of treatment, all 30 patients who could evaluate efficacy achieved CHR, of which 17 patients achieved CCyR, 18 patients showed BCR-ABL IS ≤1% and 16 patients reached MMR. After 12 months of treatment, all 17 patients were evaluated for efficacy, all achieved CHR, 10 patients obtained CCyR, 7 patients reached MMR. Grade III or IV thrombocytopenia, leukopenia and anemia occurred in 7, 2 and 1 patients, respectively. The non-hematological adverse reactions were diarrhea in 6 cases, renal function damage in 4 cases, rash and pruritus in 3 cases, liver function damage in 3 cases, nausea in 1 case, fever in 1 case, bone/joint or muscle pain in 1 case., Conclusion: In the real world, China-made flumatinib mesylate has a positive short-term efficacy and reliable safety in the treatment of CML-CP patients, whether as first-line treatment or second- and third-line conversion therapy.

Cisplatin is one of the most effective chemotherapy drugs for ovarian cancer, but resistance is common. The initial response to platinum‑based chemotherapy is as high as 80%, but in most advanced patients, final relapse and death are caused by acquired drug resistance. The development of resistance to therapy in ovarian cancer is a significant hindrance to therapeutic efficacy. The resistance of ovarian cancer cells to chemotherapeutic mechanisms is rather complex and includes multidrug resistance, DNA damage repair, cell metabolism, oxidative stress, cell cycle regulation, cancer stem cells, immunity, apoptotic pathways, autophagy and abnormal signaling pathways. The present review provided an update of recent developments in our understanding of the mechanisms of ovarian cancer platinum‑based chemotherapy resistance, discussed current and emerging approaches for targeting these patients and presented challenges associated with these approaches, with a focus on development and overcoming resistance.

Medulloblastoma (MB) is the most common type of malignant childhood brain tumor. We previously showed that inhibitors of apoptosis proteins (IAP) small-molecule inhibitors (LCL161 or LBW242) combined with chemotherapy have synergistic antiproliferative effects on MB cells. The synergistic antitumor effects of combination treatments happen through induction of autophagy and caspase-3/7-activated apoptosis. Here, we investigated the effects of IAP inhibitors or silencing IAP on cell cycle regulation. We discovered that treatment with IAP inhibitors or their combination with conventional chemotherapy (vincristine or cisplatin), as well as RNAi knockdown of cIAP1/2 or XIAP arrested MB cells in the G2/M phase through downregulation of cyclin B1-CDK1 and cyclin A-CDK1/2. Among these three IAPs, only silencing cIAP1 expression enhanced p21 dependent-G2/M phase accumulation. IAP inhibitors reduced cIAP1 expression and increased p21 expression in time course experiments. Furthermore, cIAP1 can govern p21 proteasomal degradation via neddylation in lieu of ubiquitination. Inhibition of IAPs significantly abrogated cIAP1-mediated p21 degradation. We also observed an inverse correlation between nuclear cIAP1 and nuclear p21 expressions in MB tumor tissues. These findings provide new mechanistic evidence of the influence of IAP inhibitors on MB cell proliferation through disruption of the cell cycle., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Cisplatin resistance remains a major problem in the treatment of lung cancer. We have discovered that cisplatin resistant (CR) lung cancer cells, regardless of the signaling pathway status, share the common parameter which is an increase in reactive oxygen species (ROS) and undergo metabolic reprogramming. CR cells were no longer addicted to the glycolytic pathway, but rather relied on oxidative metabolism. They took up twice as much glutamine and were highly sensitive to glutamine deprivation. Glutamine is hydrolyzed to glutamate for glutathione synthesis, an essential factor to abrogate high ROS via xCT antiporter. Thus, blocking glutamate flux using riluzole (an amyotropic lateral sclerosis approved drug) can selectively kill CR cells in vitro and in vivo. However, we discovered here that glutathione suppression is not the primary pathway in eradicating the CR cells. Riluzole can lead to further decrease in NAD+ (nicotinamide adenine dinucleotide) and lactate dehydrogenase-A (LDHA) expressions which in turn further heightened oxidative stress in CR cells. LDHA knocked-down cells became hypersensitive to riluzole treatments and possessed increased levels of ROS. Addition of NAD+ re-stabilized LDHA and reversed riluzole induced cell death. Thus far, no drugs are available which could overcome cisplatin resistance or kill cisplatin resistant cells. CR cells possess high levels of ROS and undergo metabolic reprogramming. These metabolic adaptations can be exploited and targeted by riluzole. Riluzole may serve as a dual-targeting agent by suppression LDHA and blocking xCT antiporter. Repurposing of riluzole should be considered for future treatment of cisplatin resistant lung cancer patients.

Autophagy, a self-eating machinery, has been reported as an adaptive response to maintain metabolic homeostasis when cancer cells encounter stress. It has been appreciated that autophagy acts as a double-edge sword to decide the fate of cancer cells upon stress factors, molecular subtypes, and microenvironmental conditions. Currently, the majority of evidence support that autophagy in cancer cells is a vital mechanism bringing on resistance to current and prospective treatments, yet whether autophagy affects the anticancer immune response remains unclear and controversial. Accumulated studies have demonstrated that triggering autophagy is able to facilitate anticancer immunity due to an increase in immunogenicity, whereas other studies suggested that autophagy is likely to disarm anticancer immunity mediated by cytotoxic T cells and nature killer (NK) cells. Hence, this contradiction needs to be elucidated. In this review, we discuss the role of autophagy in cancer cells per se and in cancer microenvironment as well as its dual regulatory roles in immune surveillance through modulating presentation of tumor antigens, development of immune cells, and expression of immune checkpoints. We further focus on emerging roles of autophagy induced by current treatments and its impact on anticancer immune response, and illustrate the pros and cons of utilizing autophagy in cancer immunotherapy based on preclinical references., Competing Interests: The authors declare no conflict of interest.

Background: Medulloblastoma (MB) is the most common pediatric primary malignant brain tumor. Approximately one-third of MB patients succumb to treatment failure and some survivors suffer detrimental side effects. Hence, the purpose of this study is to explore new therapeutic regimens to overcome chemotherapeutic agent resistance or reduce chemotherapy-induced toxicity., Methods: We detected the expression of inhibitors of apoptosis proteins (IAPs) in MB and CD133+ MB cell lines and MB tissues using immunoblotting and immunohistochemical staining. The antitumor effects of inhibitors against IAPs on MB or CD133+ MB cells were evaluated by MTT assay, Annexin V/PI analysis, and caspase-3/7 activity. Autophagy was assessed by the conversion of light chain (LC) 3-I to LC3-II and Cyto-ID autophagy detection kit., Results: MB cells showed higher expression of IAPs compared to normal astrocytes and normal brain tissues. Conventional chemotherapeutic agents combined with small-molecule IAP inhibitors (LCL161 or LBW242) showed a synergistic effect in MB cells. Combined treatments triggered apoptosis in MB cells through activation of caspase-3/7 and autophagic flux simultaneously. In addition, we found that CD133+ MB cells with features of cancer stem cells displayed higher levels of X-linked inhibitor of apoptosis (XIAP) and cellular inhibitor of apoptosis 1/2 (cIAP1/2), and were hypersensitive to treatment with IAP inhibitors., Conclusions: These results shed light on the biological effects of combination therapy on MB cells and illustrate that IAP inhibitors are more effective for CD133+ stem-like MB cells.

Two new complexes, Zn(L)2(H2O)2 (1) and Mn(L)2(H2O)2 (2) [L = 2-Methyl-1H-4,5-imidazoledicarboxylic acid] were synthesized and characterized by elemental analysis, infrared spectroscopy, and single crystal X-ray diffraction. Intramolecular weak interactions, such as hydrogen-bond and intermolecular interactions were presented in the complexes. The activities of the complexes binding with DNA, and cytotoxic activities were studied. The binding of complexes with fish sperm DNA (FS-DNA) was investigated by fluorescence spectra. Gel electrophoresis assay demonstrated the ability of the complexes to cleave the pBR322 plasmid DNA. The cytotoxic activities of the complexes were tested against the KB cell line. Cytotoxic activity studies showed the two complexes exhibited significant cancer cell inhibitory rate. The most active compound was complex 1 with IC50 and CC50value of 36.5, 429, with the selectivity index (SI = 11.75) among the tested compounds., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

A series of complexes [Pd(L1)(Phen)]·2H2O (1), [Pd(L2)(Phen)]·H2O (2), [Pd(L3)(Phen)]·H2O (3), [Pd(L4)(Phen)]·2H2O (4) and [Pd(L5)(Phen)]·2H2O (5) were prepared. The complexes were characterized by IR, (1)H NMR, elemental analysis, and single-crystal X-ray diffractometry. The binding of the complexes was investigated by fluorescence spectrum and UV spectrum, showing the ability of interaction with DNA of intercalative mode. Gel electrophoresis assay demonstrated the ability of the complexes to cleave the pBR322 DNA. Moreover, the five complexes bind to DNA with different binding affinities, in ascending order: complex 1 < 2<3 < 4 < 5. Evaluation of cytotoxic activity of the complexes against five different cancer cell lines proved that the complexes exhibited cytotoxic specificity and significant cancer cell inhibitory rate., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Zoledronic acid (ZOL), a nitrogen-containing compound, is effective in the treatment of skeletal disorders, but its long-term use in high doses gives rise to complications such as osteonecrosis. We aimed to investigate the effect of low-dose ZOL on the expression of the neural cell adhesion molecule (NCAM), which may be correlated with tumor growth and spinal cord metastasis in lung adenocarcinoma with neuroendocrine differentiation. First, we used the small hairpin RNA technique to directly knock down NCAM expression in cells of a murine lung adenocarcinoma line, line 1 cells, and found that the tumor cells generated showed lower invasive capacity, slower tumor growth, and lesser tendency for spinal cord metastasis than control cells. Further, ZOL decreased NCAM expression and invasiveness in line 1 tumor cells in vitro. Line 1/lacZ cells, a stable clone tagged with the lacZ gene, were introduced into mice, followed by ZOL treatment (1 μg/kg/weekly). Low-dose ZOL significantly reduced spinal cord metastasis probably through reduced NCAM expression in vivo. These findings indicated that NCAM is involved in tumor growth and spinal cord metastasis of lung adenocarcinoma with neuroendocrine differentiation. Treatment with low-dose ZOL can reduce NCAM expression that may contribute toward reduced spinal cord metastasis, suggesting that NCAM is an alternative therapeutic target and that the low-dose ZOL treatment protocol is a reasonable approach for its treatment.

Background: Although arsenic trioxide (ATO) has displayed anticancer activity against primary nasopharyngeal carcinoma (NPC), its efficacy in metastatic NPC deserved further investigation because the biological/therapeutic difference in cancer cells probably exists between primary and distant sites., Methods: Two human metastatic NPC cell lines (NPC-BM1 and NPC-BM2) were investigated. We measured cellular proliferation, cell cycle, and apoptotic extent of BM1 and BM2 cells treated with ATO in vitro. Furthermore, we evaluated the tumor growth after ATO treatment in vivo., Results: Low-dose ATO treatment is sufficient to induce an antiproliferative effect, alter the cell cycle, and increase apoptosis in BM1 and BM2 cells. BM1 tumor growth in a xenograft model with low-dose and short-schedule (1 mg/kg/day, intraperitoneal injection for 5 consecutive days) of ATO treatment significantly slowed in vivo., Conclusion: ATO at low dose seems to be an encouraging schedule for palliative treatment of metastatic NPC., (Copyright © 2010 Wiley Periodicals, Inc.)

Abstract: Objectives: To investigate the antitumour property of tetrandrine by inducing autophagy and apoptosis in human gastric cancer cells, and to explore the potential molecular mechanisms. Methods: The antitumour activity of tetrandrine was assessed through MTT assay. Apoptosis was measured by flow cytometry and microscopic examination of cellular morphology. The mitochondrial membrane potential was detected by staining with Rh‐123. Induction of autophagy was monitored by transmission electron microscopy observation, using GFP‐LC3 transfection. Key findings: The results revealed that tetrandrine exhibits significant antitumour activity against gastric human cancer cell and the antigastric tumour activity was depended on inducing autophagy and apoptosis through upregulating the apoptosis‐related protein (cleaved PARP, cleaved caspase‐3 and cleaved caspase‐9) and autophagy‐related protein (Beclin‐1, LC3‐II and p62), and decreasing the phosphorylation of AKT/mTOR, PS6K and P‐4EBP1. Adding the inhibitor of autophagy, 3‐MA or Baf‐A1, increased the viability of tetrandrine‐exposed gastric cancer cells, which confirmed the role of autophagy played in the gastric cancer cell death induced by tetrandrine. Conclusions: These results demonstrated that the antitumour effects of tetrandrine by inducing autophagy and apoptosis involving Akt/mTOR pathway. Thus, tetrandrine may be a promising lead compound to be further developed in future for cancer therapy. [ABSTRACT FROM AUTHOR]

Two new triterpenoid saponins (1, 2) and a known saponin (3) were isolated from the husks of Xanthoceras sorbifolia Bunge., and their structures were elucidated as 3-O-β-d-glucopyranosyl(1 → 6)-[angeloyl(1 → 2)]-β-d-glucopyranosyl-28-O-α-l-rhamnopyranosyl(1 → 2)-[β-d-glucopyranosyl(1 → 6)]-β-d-glucopyranosyl-21β,22α-dihydroxyl-olean-12-ene (1), 3-O-β-d-glucopyranosyl-28-O-[β-d-glucopyranosyl(1 → 2)]-β-d-glucopyranosyl-21β,22α-dihydroxyl-olean-12-ene (2), and 3-O-β-d-glucopyranosyl-28-O-[α-l-rhamnopyranosyl(1 → 2)]-β-d-glucopyranosyl-21β,22α-dihydroxyl-olean-12-ene (3), on the basis of the spectral analysis of NMR and chemical methods. Cytotoxic assay indicated that none of them showed obvious inhibitory effect on the proliferation of two human tumor cell lines. [ABSTRACT FROM PUBLISHER]

Abstract: Patients with non-small cell lung carcinoma (NSCLC) bearing epidermal growth factor receptor (EGFR) gene mutations are good responders to gefitinib (Iressa), an EGFR tyrosine kinase inhibitor (EGFR-TKI), yet these patients may eventually develop acquired resistance to all available EGFR-TKIs. Nitrogen-containing bisphosphonates (N-BPs) are inhibitors of farnesyl diphosphate (FPP) synthase as well as chelators of divalent cations. This study was undertaken to examine if the N-BP zoledronic acid (zoledronate) possessing antitumor activity could enhance the antitumor effect of gefitinib on the HCC827 NSCLC cell line expressing mutated EGFR. Both gefitinib and zoledronate were cytotoxic to HCC827 cells when treated alone. Combined treatment with gefitinib (0.025μM) that induced G 0/G 1 arrest and zoledronate (50μM) that caused S/G 2/M accumulation generated an additive induction in cell cytotoxicity, sub-G 1 cell population, and apoptosis. Gefitinib suppressed EGF-activated phosphorylation of ERK1/2 and Akt, while zoledronate seemed to impose its pharmacological effect independent of ERK1/2 and Akt phosphorylation. The volumes of xenografted tumors in nude mice co-administered with gefitinib (1mg/kg/day, five days a week, p.o.) and zoledronate (10μg/kg, twice weekly, i.p.) were significantly smaller than those of tumors in mice treated with gefitinib alone at the last stage of a 6-week in vivo study. Severe peri-tumoral fat loss frequently observed in gefitinib-treated mice disappeared in mice receiving the combined treatment. Hence, combined treatment of gefitinib with zoledronate may form a basis to develop a more effective and less toxic therapy for NSCLC with EGFR gene mutations. [Copyright &y& Elsevier]