Potential Antineoplastic Agents Research Articles

Biodegradable system for drug delivery of hydrolytically labile azanucleoside drugs.

The archetypal DNA methyltransferase inhibitors, 5-azacytidine (AZA) and 5-aza-2'-deoxycytidine (DAC) are potent antineoplastic agents used in the treatment of mainly, blood malignancies. However, the administration of these drugs is confounded by their hydrolytic lability which decreases plasma circulation time. Here, we describe a new biodegradable, polyanhydride formulation for drug delivery that circumvents this drawback. Injectable/implantable polymeric microbeads containing dispersed microcrystals of hydrophilic AZA or DAC packed in a dry environment are protected from hydrolysis, until the hydrolytic zone reaches the core. Diclofenac is embedded into the formulation to decrease any local inflammation. The efficacy of the formulations was confirmed by monitoring the induced demethylation, and cytostatic/cytotoxic effects of continuous drug release from the time-course dissolution of the microbeads, using an in vitro developed cell based reporter system. Poly(sebaccic acid-co-1,4-cyclohexanedicarboxylic acid) containing 30 wt. % drug showed zero-order release (R(2) = 0.984 for linear regression), and release rate of 10.0 %/h within the first 5 h, and subsequent slower release of the remaining drug, thus maintaining the level of drugs in the outer environment considerably longer than the typical plasma half-life of free azanucleosides. At lower concentrations, the differences between powder drug formulations and microbeads were very low or negligible, however, at higher concentrations, we discovered equivalent or increasing effects of the drugs loaded in microbeads. The study provides evidence that microbead formulations of the hydrolytically labile azanucleoside drugs could prevent their chemical decomposition in aqueous solution, and effectively increase plasma circulation time.

Bisphosphonates as potential adjuvants for patients with cancers of the digestive system.

Best known for their anti-resorptive activity in bone, bisphosphonates (BPs) have generated interest as potential antineoplastic agents given their pleiotropic biological effects which include antiproliferative, antiangiogenic and immune-modulating properties. Clinical studies in multiple malignancies suggest that BPs may be active in the prevention or treatment of cancer. Digestive tract malignancies represent a large and heterogeneous disease group, and the activity of BPs in these cancers has not been extensively studied. Recent data showing that some BPs inhibit human epidermal growth factor receptor (HER) signaling highlight a potential therapeutic opportunity in digestive cancers, many of which have alterations in the HER axis. Herein, we review the available evidence providing a rationale for the repurposing of BPs as a therapeutic adjunct in the treatment of digestive malignancies, especially in HER-driven subgroups.

Lac dye as a potential anti-neoplastic agent.

Certain anthraquinone compounds are effectively used for treatment of cancer. The present study describes the inhibitory activity of lac dye, a mixture of polyhydroxy anthraquinone compounds (Laccaic acid A, B, C, D and E), produced by the Indian lac insect, Kerria lacca (Kerr). In vitro testing for anticancer activity of lac dye was done at four concentrations (10, 20, 40, 80 μg/ml) on ten human malignant cell lines including six human leukemia cell lines, U973, Raji, K562, Jurkat, MOLT 4 and HL60 using SRB assay. Both crimson and yellow lac dye inhibits proliferation of Human leukemia cell lines, Raji, U937, K562, HL60 and Jurkat, therefore can be considered as a potential anticancer agent for leukemia.

Successful treatment of angioimmunoblastic T-cell lymphoma with clarithromycin.

TO THE EDITOR: Macrolide antibiotics (Macs) have been proposed as potential antineoplastic and immunomodulatory agents in addition to their primary role as antibacterial agents. They have anti-lymphoproliferative effects and are clinically applicable for treating lymphoid malignancies. Several previous reports have indicated that B-cell malignancies can be treated successfully with Macs [1,2,3]. With regard to T-cell lineage malignancies, we have reported previously a case of mixed phenotype acute leukemia, T/myeloid, not otherwise specified, treated successfully using clarithromycin (CAM), a Mac, in combination with prednisolone (PSL) [4]. Here, we report the first case of angioimmunoblastic T-cell lymphoma (AITL) treated successfully with CAM in combination with PSL.

Cytotoxic effects of peanut phenolic compounds possessing histone deacetylase inhibitory activity on human colon cancer cell lines

Phenolic compounds present in our diet play an important role in colon cancer chemoprevention. Previous results demonstrated that peanut testa extract inhibited both histone deacetylase (HDAC) activity and the growth of colon cancer cells. In this study, four identified phenolic compounds in peanut testae (resveratrol, p-coumaric acid, ferulic acid, and sinapinic acid) were investigated for their HDAC inhibitory and anticancer activities against colon cancer cell lines. In vitro study revealed that resveratrol exhibited the greatest HDAC inhibitory activity. Molecular docking studies demonstrated that all four compounds could bind both HDAC1 and HDAC2. Resveratrol exhibited the most effective antiproliferative activity against both human colon adenocarcinoma (HT29) and human colorectal carcinoma (HCT116) cells. Apoptosis induction by ferulic acid and resveratrol appeared to be associated with p53 activation in HCT116 cells. However, resveratrol, p-coumaric acid, ferulic acid, and sinapinic acid induced apoptosis of HT29 cells in a p53-independent manner. Low-concentration treatments of p-coumaric and ferulic acids resulted in cell cycle arrest of HCT116 cells. In contrast, high-concentration treatments of p-coumaric and ferulic acids showed cell death activation as evidenced by increased sub-G1 fractions. The induction of p21 by p-coumaric acid and resveratrol correlated well with the decreased CDK4 levels and cell cycle arrest. Resveratrol, p-coumaric acid, ferulic acid, and sinapinic acid caused activation of pERK1/2 in HCT116 cells, whereas ferulic and sinapinic acids caused downregulation of pERK1/2 in HT29 cells. These results suggest that these peanut phenolics may be potential antineoplastic agents for colon cancer chemoprevention/chemotherapy.

Dimethylsulfoxide excerbates cisplatin-induced cytotoxicity in Ehrlich ascites carcinoma cells.

BackgroundCisplatin (CIS) is a potent antineoplastic agent with high therapeutic efficacy against many kinds of tumors. Its use is limited by its nephrotoxicity. The aim of this work was to minimize cisplatin effective dose and the possible reduction of its severe side effects. The present study was designed to assess the role of sulfur containing agent dimethyl sulfoxide (DMSO) on sensitization of mammary carcinoma, Ehrlich ascites carcinoma (EAC), to the action of cisplatin and at the same time the possible protective effect against cisplatin induced nephrotoxicity in experimental animals.MethodsTo evaluate these effects we have explored the cisplatin effect on the survival time of tumor-bearing animals, tumor weight, cisplatin cellular uptake, apoptosis induction and cell cycle distribution and renal function in presence and absence of DMSO.ResultsCisplatin at dose of 4.5 mg/kg increased the mean survival time of tumor bearing mice to 37 days compared with tumor bearing control mice. Pretreatment of tumor bearing mice with DMSO 50 % (2 ml/kg equal to 1 gm/kg) 2 h. before cisplatin showed a significant increase in their mean survival time 43 days compared to cisplatin treated animals. DMSO pretreatment retained rat’s serum urea and creatinine levels to normal compared to animals treated with cisplatin alone.ConclusionDMSO pretreatment enhanced the cytotoxic activity of cisplatin against the growth of EAC in vivo and showed protective effects against cisplatin-induce nephrotoxicity.

Anticancer Effects of Curcuma C20-Dialdehyde against Colon and Cervical Cancer Cell Lines.

Recent attention on chemotherapeutic intervention against cancer has been focused on discovering and developing phytochemicals as anticancer agents with improved efficacy, low drug resistance and toxicity, low cost and limited adverse side effects. In this study, we investigated the effects of Curcuma C20-dialdehyde on growth, apoptosis and cell cycle arrest in colon and cervical cancer cell lines. Antiproliferative, apoptosis induction, and cell cycle arrest activities of Curcuma C20-dialdehyde were determined by WST cell proliferation assay, flow cytometric Alexa fluor 488-annexin V/propidium iodide (PI) staining and PI staining, respectively. Curcuma C20 dialdehyde suppressed the proliferation of HCT116, HT29 and HeLa cells, with IC50 values of 65.4±1.74 μg/ml, 58.4±5.20 μg/ml and 72.0±0.03 μg/ml, respectively, with 72 h exposure. Flow cytometric analysis revealed that percentages of early apoptotic cells increased in a dose-dependent manner upon exposure to Curcuma C20-dialdehyde. Furthermore, exposure to lower concentrations of this compound significantly induced cell cycle arrest at G1 phase for both HCT116 and HT29 cells, while higher concentrations increased sub-G1 populations. However, the concentrations used in this study could not induce cell cycle arrest but rather induced apoptotic cell death in HeLa cells. Our findings suggest that the phytochemical Curcuma C20-dialdehyde may be a potential antineoplastic agent for colon and cervical cancer chemotherapy and/or chemoprevention. Further studies are needed to characterize the drug target or mode of action of the Curcuma C20-dialdehyde as an anticancer agent.

Pattern of cardiac surveillance among patients with lymphoma receiving anthracycline-based chemotherapy

ObjectiveAnthracyclines are potent antineoplastic agents in the treatment of lymphoid malignancies, but their therapeutic benefit is limited by cardiotoxicity. The American Heart Association (AHA) recommends routine surveillance, early diagnosis and...

Spiro- and substituted tetrahydrobenzo[b]thiophene-triazaphospholes and phosphoramidates as potent antineoplastic agents: synthesis, biological evaluation, and SAR studies

New and efficient conjugate addition reaction of trimethyl, triethyl, and triisopropyl phosphites with 2-azido-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile was developed and furnished spiro-triazaphosphole-oxide derivatives in ≈70 % yield. Contrary to these results, linear substituted phosphoramidates were obtained from the reaction of the azide with dimethyl, diethyl, and diisopropyl phosphites. N-Alkylamino- or 2-aminotetrahydrobenzo[b]thiophene-3-carbonitrile was also isolated in ~10 % yield from the previous two reactions. In the context of this work, hexaalkylphosphorus triamides were caused to react with the same substrate afforded the corresponding phosphoric triamides only in the presence of a protonating agent (dil. alcohol). The three reactions proceeded smoothly, cleanly, and were completed within ~6 h at r.t. Pharmacological evaluation results of antibreast, anticolon, and antiprostate carcinoma cell lines properties for the products were discussed in terms of structure–activity relationship to define a chromophore for lead compounds.

Metformin inhibits the proliferation, metastasis, and cancer stem-like sphere formation in osteosarcoma MG63 cells in vitro.

Metformin is an oral drug that has been widely used to treat type 2 diabetes mellitus. Interestingly, accumulated evidence indicate that metformin may reduce the risk of cancer in patients with type 2 diabetes and inhibit tumor cell growth and survival in numerous malignancies, including osteosarcoma (OS) cells. In the present study, we aimed to investigate the effects of metformin on the proliferation, migration, invasion, and sphere formation in OS MG63 cells in vitro. Metformin suppressed OS MG63 cell proliferation in a dose- and time-dependent manner and markedly blocked anti-metastatic potentials, migration, and invasion, by downregulating matrix metalloproteinase 2 (MMP2) and MMP9. Besides, we established OS cancer stem-like cell (CSC) model with sarcosphere formation assay and demonstrated that metformin posed damage on CSCs in OS by inhibiting sphere formation and by inducing their stemness loss. The stemness of CSCs in OS such as self-renewal and differentiation potentials was both impaired with a significant decrease of Oct-4 and Nanog activation. Consistent with this, the positive rates of CD90, CD133, and stage-specific embryonic antigen-4 (SSEA-4) were all observed with reductions in response to metformin exposure. In addition, Western blot showed that metformin activated AMPKα at Tyr172, followed by a downregulated phosphorylation of mammalian target of rapamycin (mTOR)/S6 and feedback activation of p-AKT Ser(473) in both OS MG63 cells and CSCs. This indicates that AMPK/mTOR/S6 signaling pathway might be involved in the growth inhibition of both OS MG63 cells and CSCs. These results suggest that metformin, a potential anti-neoplastic agent, might make it a novel therapeutic choice for the treatment of OS in the future.

Joint Surface-Active Phospholipid-Mimetic Liposomes for Intra-Articular Delivery of Paclitaxel.

Synovial inflammation, angiogenesis and joint degradation are the hallmarks of inflammatory arthritis progression. Angiostatic targeting is an extensively studied potential therapeutic option for inflammatory arthritis. Studies have confirmed that surface-active phospholipids (SAPLs), predominantly phosphatidylcholines (PCs), are responsible for the lubricating properties of lubricin in joints. Paclitaxel, a potent antineoplastic agent in cancer chemotherapy, has been shown to inhibit several processes associated with arthritis development such as angiogenesis, neutrophil activation and collagenase expression but is limited by systemic toxicity. This study was aimed at designing a surface-active phospholipid mimetic nanocarrier system and assessing its efficacy for intra-articular delivery of paclitaxel in rat joints. Dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) liposomes were prepared using a thin-film hydration method and characterized for size, morphology, drug encapsulation and in vitro release. DPPC liposomes of a size of 311 ± 57 nm and 92 ± 0.6% paclitaxel encapsulation were developed. In vitro release studies showed a short initial burst phase and a sustained release profile with a cumulative release of 18 ± 0.36% of the drug by 60 h in phosphate-buffered saline (PBS). The efficacy of the intra-articular formulation was evaluated in antigen-induced arthritic rat models and compared with direct injections of paclitaxel. After a 28-day period, intra-articular paclitaxel delivered in liposomes led to a significant improvement in gait scores and synovial inflammation in rats compared to the control, as seen in histopathology studies. Reduction in inflammation in the experimental group was confirmed by evaluating TNFα levels in serum samples. This study suggests feasibility of using surface-active phospholipid based carriers for local, intra-articular therapy of paclitaxel in arthritis.

Effect of Doxorubicin and Some Boron Compounds on Erythrocyte Fragility In Rats

Objective: Doxorubicin is a potent antineoplastic agent used in chemical treatment of cancer. However due to their cardiotoxic effects, its use is limited and currently subject for extensive research. Cardiomyopathy caused by doxorubicin still remains as a major concern for this potent drug. This study was aimed to contribute to this issue which needs novel preventive treatment for this side effect. Materials and Methods: Boron and boron containing molecules are subject of medical research due to their properties such as antioxidant nature. They are tested in various diseases and experimental setups. In this study Boric acid, Potassium tetraborate, Amonium biborat tetrahidrat was given to male rats at 10 mg/kg/day for 6 weeks. All study groups (n=8 each) received Doxorubicin and Boron containing compounds via intraperitoneal route. Following 6 weeks blood was withdrawn and erythrocyte osmotic fragility test was applied. Results: Erythrocyte fragility values of all doxorubicin containing groups increases and become significant at 0.5, 0.6, 0.7 and 0.8% NaCl concentrations (p<0.05). Among doxorubicin groups no significant difference was observed. Results of this study suggests that doxorubicin increases erythrocyte osmotic fragility and boron containing molecules are not sufficient to recover this untoward effect on erythrocytes at the applied dosage. Conclusion: Possible mechanisms of this result and testing in a dose dependent manner can be tested in future studies.

Structurally diverse c-Myc inhibitors share a common mechanism of action involving ATP depletion.

The c-Myc (Myc) oncoprotein is deregulated in a large proportion of diverse human cancers. Considerable effort has therefore been directed at identifying pharmacologic inhibitors as potential anti-neoplastic agents. Three such groups of small molecule inhibitors have been described. The first is comprised of so-called "direct" inhibitors, which perturb Myc's ability to form productive DNA-binding heterodimers in association with its partner, Max. The second group is comprised of indirect inhibitors, which largely function by targeting the BET-domain protein BRD4 to prevent the proper formation of transcriptional complexes that assemble in response to Myc-Max DNA binding. Thirdly, synthetic lethal inhibitors cause the selective apoptosis of Myc over-expressing either by promoting mitotic catastrophe or altering Myc protein stability. We report here a common mechanism by which all Myc inhibitors, irrespective of class, lead to eventual cellular demise. This involves the depletion of ATP stores due to mitochondrial dysfunction and the eventual down-regulation of Myc protein. The accompanying metabolic de-regulation causes neutral lipid accumulation, cell cycle arrest, and an attempt to rectify the ATP deficit by up-regulating AMP-activated protein kinase (AMPK). These responses are ultimately futile due to the lack of functional Myc to support the requisite anabolic response. Finally, the effects of Myc depletion on ATP levels, cell cycle arrest, differentiation and AMPK activation can be mimicked by pharmacologic inhibition of the mitochondrial electron transport chain without affecting Myc levels. Thus, all Myc inhibitors promote a global energy collapse that appears to underlie many of their phenotypic consequences.

Marizomib, a potent second generation proteasome inhibitor from natural origin.

The malignance of cancers reinforces the need to find potent antineoplastic agents. In the past decades, proteasome has been witnessed as a potential target to fulfil this purpose, as evidenced by the fact that the first-in-class proteasome inhibitor Bortezomib was marketed in 2003. Marizomib (Salinosporamide A, NPI-0052), as a marine natural product, promises to be of high efficacy against multiple myeloma (MM), relapsed/refractory MM and other types of solid tumours. Compared with Bortezomib, it arguably has fewer severe side effects. Marizomib has been termed as orphan drug against multiple myeloma by US Food and Drug Administration (FDA) in 2013 and by European Medicines Agency (EMA) in 2014. As one of the second generation proteasome inhibitors (PIs), Marizomib is expected to bring about a sustained and complete therapeutic to extend cancer patients' life span. In this article, we intended to briefly review the historical developments, mechanisms, pharmacology, biosynthesis and side effects of this agent, aiming to provide concise coverage for a broad readership. In the end, we proposed our perspective for its futuristic applications.

Pentoxifylline Prevents Driamycin-Induced Myocardial Fibrosis and Apoptosis in Rats.

Adriamycin (ADR) is a potent antineoplastic agent, but long-term treatment is limited by its cumulative, life-threatening cardiomyopathy. Recently, a few reports have shown that pentoxifylline (PTX) might produce cardioprotection in cardiac dysfunction. Here, we investigated the protective effects of PTX on ADR-induced cardiomyopathy in rats. Male rats were randomly assigned either to saline, ADR (adriamycin, 5 mg/kg/week), or A (adriamycin, 5 mg/kg/week) + PTX (pentoxifylline, 50 mg/kg/day) groups. After 3 weeks, these animals were sacrificed and the heart tissue was harvested for histological analysis and assessment of hepatocyte growth factor (HGF) and caspase-3 expression. Histopathological findings showed that PTX can alleviate myocardial damage caused by ADR. Cardiac fibrosis was significantly suppressed in the A+PTX group compared to that in the ADR group. The HGF gene expression was decreased significantly in the ADR group compared with the control group, but was increased in the A+PTX group. Caspase-3 was up-regulated in the ADR group, and down-regulated in the A+PTX group. These results show that treatment with PTX exerts a protective effect against ADR-induced myocardial fibrosis via regulation of HGF and caspase-3 gene expression. PTX may thus represent a useful new clinical tool for the treatment of ADR-induced cardiomyopathy.

Application of Mannich bases to the synthesis of hydroxymethylated isoflavonoids as potential antineoplastic agents.

The regiospecific Mannich aminomethylation of 7-hydroxyisoflavonoids using bis(N,N-dimethylamino)methane afforded C-8 substituted N,N-dimethylaminomethyl adducts, and the regioselective aminomethylation of 5-hydroxy-7-methoxyisoflavonoids afforded predominantly the C-6 substituted N,N-dimethylaminomethyl adducts. Acetylation of these C-6 or C-8 Mannich bases with potassium acetate in acetic anhydride provided access to the corresponding acetoxymethyl derivatives that were subsequently converted to hydroxymethyl- and methoxymethyl-substituted 5-hydroxy- or 7-hydroxyisoflavonoids related to naturally occurring flavonoids. The C-8 acetoxymethyl, hydroxymethyl or methoxymethyl-substituted isoflavonoids possessed promising inhibitory potency in the low micromolar range in a prostate cancer PC-3 cell proliferation assay.

Abstract 1790: Small molecule inhibitors of QSOX1 suppress tumor cell growth and invasion

Abstract Introduction: QSOX1 is a flavin-dependent sulfhydryl oxidase and the only known human enzyme with both disulfide generating and transferring activities. Using tissue microarrays, we previously demonstrated that QSOX1 is over-expressed in multiple tumor types including breast, pancreas, prostate and myeloma. Loss of QSOX1 leads to a significant decrease in tumor cell proliferation and invasion. The over-expression of QSOX1 in tumor cells compared to non-malignant cells combined with its role in tumor cell proliferation and invasion make it an attractive target for potential anti-neoplastic agents. Methods: Using a high throughput screening assay to detect sulfhydryl oxidase activity, we screened a library of compounds for inhibition of the QSOX1 enzyme. We used ROS-GloTM, a luciferase-based assay that detects H2O2, to determine if any compounds in the library inhibited QSOX1-mediated disulfide bond formation using reduced RNAse A as a substrate. QSOX1 generates H2O2 as a by-product of disulfide bond formation. To determine if compounds that showed activity in the enzymatic assay were also active against tumor cells, we treated pancreatic, breast, and myeloma cells with the compounds in a dose-dependent fashion, using non-malignant cells as controls. We assayed growth/viability by MTT and CellTiter-Glo assays. Invasive activity of tumor cells was assessed using matrigel-coated inserts in a modified Boyden chamber assay. Results: High throughput library screening identified 4 compounds that specifically inhibited QSOX1 activity (designated A-D) compared to a glucose oxidase counter-screen. Growth/viability assays showed that compound D suppressed the growth of tumor cells with IC50s between 300nM-750nM, depending on tumor cell line. In non-malignant cells the IC50s for compound D were more than 10-fold higher than in tumor cells. Compounds A and D also inhibited invasion of breast and pancreatic tumor cells through Matrigel. Conclusion: This is the first report of chemical compounds that inhibit QSOX1 enzymatic activity. The discovery of QSOX1 inhibitors with cellular efficacy establishes the chemical tractability of the target. Our data demonstrate that these First-In-Class compounds have potential as anti-neoplastic therapeutics via inhibition of QSOX1. Citation Format: Paul D. Hanavan, Douglas O. Faigel, Chen-Ting Ma, Eduard Sergienko, Nathalie Meurice, Joachim L. Petit, Yvette W. Ruiz, Benjamin A. Katchman, Douglas F. Lake. Small molecule inhibitors of QSOX1 suppress tumor cell growth and invasion. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1790. doi:10.1158/1538-7445.AM2014-1790

Abstract 190: Predictors and Outcome of Anthracycline-induced Cardiomyopathy among Lymphoma Patients

Background: Anthracyclines (AC) are one of the most potent anti-neoplastic agents in the treatment of lymphoid malignancies. However their therapeutic benefit is limited by cardiotoxicity. Among patients receiving AC, it is unclear whether traditional cardiovascular markers predict cardiomyopathy (CMP) and whether patients with AC-CMP have higher mortality compared with non-CMP patients. Methods: We performed a retrospective analysis of a cohort of Non-Hodgkin lymphoma (NHL) patients evaluated by the Emory Lymphoma program who received AC between 1992 and 2013. We assessed cardiac function by echocardiogram or equilibrium radionuclide imaging. We examined the prevalence of AC-CMP (defined as an absolute decrease in LVEF &gt; 10% with a decline &lt;50%, or an LVEF reduction of at least 15% with absolute LVEF &gt; 50%). Analyses only included patients who received assessment of LVEF both pre and post-AC. Statistical analysis was performed by univariable and multivariable logistic regression models of clinical characteristics potentially associated with a decrease in LVEF. Results: Of 218 patients who received AC (median dose 300 mg/m2), 41% (89 of 218) had imaging surveillance before and after AC. Twenty seven percent of patients had AC-CMP. In the multivariate analyses after adjusting for demographics and traditional cardiac comorbidites, among patients receiving AC, patients with tobacco abuse [OR, 2.4; 95% CI, 0.8 to 7.0; P = 0.12], coronary artery disease [OR, 2.6; 95% CI, 0.8 to 7.9; P = 0.10] and diabetes [OR, 2.9; 95% CI, 0.9 to 9.9; P = 0.08] were more likely to have CMP although the association did not reach statistical significance. Mortality among CMP patients was numerically higher compared with non-CMP patients (50% vs. 35%; P = 0.28). Conclusions: Among patients receiving AC for lymphoma, there is a trend towards increased risk of CMP in patients with history of tobacco abuse, CAD and diabetes. Additionally, AC-CMP patients had numerically higher mortality compared with non-CMP patients. Future studies are needed to confirm these important findings in larger samples to ascertain predictors and outcome of AC induced CMP in cancer patients.

Magnesium protects against cisplatin-induced acute kidney injury by regulating platinum accumulation

Despite its success as a potent antineoplastic agent, ∼25% of patients receiving cisplatin experience acute kidney injury (AKI) and must discontinue therapy. Impaired magnesium homeostasis has been linked to cisplatin-mediated AKI, and because magnesium deficiency is widespread, we examined the effect of magnesium deficiency and replacement on cisplatin-induced AKI in physiologically relevant older female mice. Magnesium deficiency significantly increased cisplatin-associated weight loss and markers of renal damage (plasma blood urea nitrogen and creatinine), histological changes, inflammation, and renal cell apoptosis and modulated signaling pathways (e.g., ERK1/2, p53, and STAT3). Conversely, these damaging effects were reversed by magnesium. Magnesium deficiency alone significantly induced basal and cisplatin-mediated oxidative stress, whereas magnesium replacement attenuated these effects. Similar results were observed using cisplatin-treated LLC-PK1 renal epithelial cells exposed to various magnesium concentrations. Magnesium deficiency significantly amplified renal platinum accumulation, whereas magnesium replacement blocked the augmented platinum accumulation after magnesium deficiency. Increased renal platinum accumulation during magnesium deficiency was accompanied by reduced renal efflux transporter expression, which was reversed by magnesium replacement. These findings demonstrate the role of magnesium in regulating cisplatin-induced AKI by enhancing oxidative stress and thus promoting cisplatin-mediated damage. Additional in vitro experiments using ovarian, breast, and lung cancer cell lines showed that magnesium supplementation did not compromise cisplatin's chemotherapeutic efficacy. Finally, because no consistently successful therapy to prevent or treat cisplatin-mediated AKI is available for humans, these results support developing more conservative magnesium replacement guidelines for reducing cisplatin-induced AKI in cancer patients at risk for magnesium deficiency.

Synthesis of novel spin-labeled podophyllotoxin derivatives as potential antineoplastic agents: Part XXV.

A series of novel spin-labeled 4β-[(4-substituted)-1,2,3-triazol-1-yl]podophyllotoxin derivatives (17a-h) were firstly designed and synthesized with significant regioselectivity by employing Cu(I) catalyzed click approach, and evaluated for cytotoxicity against four human tumor cell lines (A-549, DU145, KB, and KBvin). Among them, compound 17h displayed the highest cytotoxic activity against the tumor cell lines tested. Significantly, compound 17h showed superior cytotoxic activity compared with etoposide (IC50 6.30 to>10 μM), a clinically available anticancer drug. Significant activity toward the drug resistant KBvin cell line revealed promising future for compound 17h as a new generation of epipodophyllotoxin-derived antitumor clinical trial candidate.