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International Journal of Cancer Apr 2007Apomine, a novel 1,1 bisphosphonate ester, increases the rate of degradation of HMG-CoA reductase, inhibiting the mevalonate pathway and thereby blocking cholesterol...
Apomine, a novel 1,1 bisphosphonate ester, increases the rate of degradation of HMG-CoA reductase, inhibiting the mevalonate pathway and thereby blocking cholesterol biosynthesis. We have investigated whether Apomine can induce myeloma cell apoptosis in vitro and modulate myeloma disease in vivo. Apomine induced a dose-dependent increase in apoptosis in NCI H929, RPMI 8226 and JJN-3 human myeloma cells. Apomine, unlike the bisphosphonate, alendronate, had no measurable effect on osteoclastic bone resorption in vitro. To investigate the effect of Apomine in vivo, 5T2MM murine myeloma cells were injected into C57BL/KaLwRij mice. After 8 weeks all animals had a serum paraprotein and were treated with Apomine (200 mg/kg), or vehicle, for 4 weeks. Animals injected with 5T2MM cells and treated with vehicle developed osteolytic bone lesions, reduced cancellous bone area, decreased bone mineral density (BMD) and increased osteoclast number. Apomine caused a decrease in serum paraprotein and a decrease in tumor burden. Apomine inhibited the development of osteolytic lesions and prevented the tumor-induced decreases in BMD. Apomine had no effect on osteoclast number in contrast to what had been seen previously with the bisphosphonate, zoledronic acid, suggesting that these are direct effects of Apomine on myeloma cells. This demonstrates that Apomine is able to promote myeloma cell apoptosis in vitro and inhibit the development of multiple myeloma and lytic bone disease in vivo. The use of bisphosphonate esters such as Apomine represents a novel therapeutic approach in the treatment of myeloma and, indirectly, the associated bone disease.
Topics: Animals; Apoptosis; Bone Density; Bone Resorption; Diphosphonates; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Multiple Myeloma; Osteoclasts; Paraproteins; Tumor Cells, Cultured
PubMed: 17230522
DOI: 10.1002/ijc.22478 -
The Journal of Biological Chemistry Feb 2004Apomine, a novel 1,1-bisphosphonate ester, has been shown to lower plasma cholesterol concentration in several species. Here we show that Apomine reduced the levels of...
Apomine, a novel hypocholesterolemic agent, accelerates degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and stimulates low density lipoprotein receptor activity.
Apomine, a novel 1,1-bisphosphonate ester, has been shown to lower plasma cholesterol concentration in several species. Here we show that Apomine reduced the levels of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR), the rate-limiting enzyme in the mevalonate pathway, both in rat liver and in cultured cells. Apomine resembles sterols such as 25-hydroxycholesterol in its ability to potently accelerate the rate of HMGR degradation by the ubiquitin-proteasome pathway, a process that depends on the transmembrane domain of the enzyme. The similarity between Apomine and sterols in promoting rapid HMGR degradation extends to its acute requirements for ongoing protein synthesis and mevalonate-derived non-sterol product(s) as a co-regulator. Yet, at suboptimal concentrations, sterols potentiated the effect of Apomine in stimulating HMGR degradation, indicating that these agents act via distinct modes. Furthermore, unlike sterols, Apomine inhibited the activity of acyl-CoA:cholesterol acyltransferase in intact cells but not in cell-free extracts. Apomine stimulated the cleavage of the precursor of sterol-regulatory element-binding protein-2 and increased the activity of low density lipoprotein receptor pathway. This Apomine-enhanced activation of sterol-regulatory element-binding protein-2 was prevented by sterols or mevalonate. Taken together, our results provide a molecular mechanism for the hypocholesterolemic activity of Apomine.
Topics: Animals; Anticholesteremic Agents; CHO Cells; Cell-Free System; Cells, Cultured; Cholesterol; Cricetinae; DNA-Binding Proteins; Diphosphonates; Dose-Response Relationship, Drug; HeLa Cells; Humans; Hydroxycholesterols; Hydroxymethylglutaryl CoA Reductases; Immunoblotting; Liver; Male; Models, Chemical; Precipitin Tests; Rats; Rats, Wistar; Receptors, LDL; Sterol Regulatory Element Binding Protein 2; Time Factors; Transcription Factors
PubMed: 14627708
DOI: 10.1074/jbc.M308094200 -
The Journal of Pharmacology and... Jul 2007Apomine, a 1,1-bisphosphonate-ester with antitumor activity, has previously been reported to strongly down-regulate 3-hydroxy-3-methylglutaryl-coenzyme A reductase...
Apomine, a 1,1-bisphosphonate-ester with antitumor activity, has previously been reported to strongly down-regulate 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), the rate-limiting enzyme in the mevalonate pathway responsible for the prenylation of proteins. Here, we show that although apomine down-regulated HMG-CoA reductase protein levels in myeloma cells, it did not inhibit protein prenylation, and apomine-induced apoptosis could not be prevented by mevalonate, indicating that apomine cytotoxicity is independent from its effects on HMG-CoA reductase. Instead, apomine cytotoxicity was prevented by the addition of phosphatidylcholine, which is similar to the previously reported ability of phosphatidylcholine to overcome the cytotoxicity of farnesol, whereas phosphatidylcholine had no effect on down-regulation of HMG-CoA reductase by apomine. These findings raised the possibility that apomine, independent from its own cytotoxic effects, could enhance the antitumor effects of the competitive HMG-CoA reductase inhibitor lovastatin via down-regulating HMG-CoA reductase. Indeed, treatment with apomine in combination with lovastatin resulted in synergistic decreases in viable cell number and induction of apoptosis. At the concentrations used, apomine down-regulated HMG-CoA reductase protein levels without being cytotoxic. Accumulation of unprenylated Rap1A by lovastatin was enhanced in the presence of apomine. Furthermore, synergy was completely prevented by mevalonate, and apomine did not synergize with desoxolovastatin, which does not inhibit HMG-CoA reductase. We conclude that the synergistic drug interaction results from an enhancement by apomine of the effects of lovastatin, mediated by down-regulation of HMG-CoA reductase by apomine. Thus, these findings demonstrate a novel strategy for enhancing the antitumor effects of lovastatin.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Diphosphonates; Down-Regulation; Drug Synergism; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin; Mevalonic Acid; Multiple Myeloma; Phosphatidylcholines; Protein Prenylation
PubMed: 17412884
DOI: 10.1124/jpet.106.116467 -
Investigational New Drugs Apr 2007Apomine, a novel bisphosphonate ester, has demonstrated anticancer activity in a variety of cancer cell lines; however, its mechanism of cytotoxicity is not well...
Apomine, a novel bisphosphonate ester, has demonstrated anticancer activity in a variety of cancer cell lines; however, its mechanism of cytotoxicity is not well understood. Previous work has demonstrated that Apomine induces cell death by activation of caspase-3 in several cancer cell types. However, we have demonstrated that Apomine induces cell death in the A375 human melanoma cell line through a novel membrane-mediated mechanism that is independent of caspase-3 activation. This mechanism of membrane lysis may apply to other bisphosphonates and may be an important mechanism for overcoming resistance to apoptosis. Interestingly, Apomine-mediated cell death in the A375 and UACC 3093 human melanoma cell lines is also independent of N-Ras farnesylation, which was a previously described mechanism of action for Apomine in other cancer cell types. These data suggest that Apomine induces cell death through a novel plasma membrane-mediated cytolytic pathway, independent of caspase-3 activation and N-Ras farnesylation.
Topics: Antineoplastic Agents; Apoptosis; Caspases; Cell Line, Tumor; Cell Membrane; Cell Survival; Cytosol; DNA, Neoplasm; Diphosphonates; Enzyme Activation; Genes, ras; Humans; Immunoblotting; L-Lactate Dehydrogenase; Melanoma; Poly(ADP-ribose) Polymerases; Thymidine; ras Proteins
PubMed: 17024575
DOI: 10.1007/s10637-006-9015-6 -
Investigational New Drugs Jan 2006Metastatic melanoma continues to be a very difficult disease to treat. Options are limited and often have very little impact on the course of the disease. The objective...
Metastatic melanoma continues to be a very difficult disease to treat. Options are limited and often have very little impact on the course of the disease. The objective of the current study was to evaluate the efficacy and safety of continuously administered Apomine (SR-45023A), a novel bisphosphonate, in patients with previously treated metastatic malignant melanoma. Adult patients with previously treated metastatic melanoma received Apomine 100 mg orally, twice daily (total dose 200 mg per day) continuously for 28 days (defined as a cycle). Treatment was continued until disease progression or unacceptable toxicity. A total of 42 patients received at least one dose of Apomine. Stable disease was achieved in 2 patients (5%). No complete or partial responses were observed. Progression free survival of at least 16 weeks was observed in 6 patients (14%). The median overall survival was 6.1 months (95% CI, 4.9-9.4 months). Time to treatment failure was 1.7 months (95% CI, 1.6-1.8 months) with Apomine therapy. By cycle 2, Apomine concentrations reached steady-state. Apomine was well tolerated with only 37% of patients experiencing any drug-related event. Abdominal pain was the most frequent adverse event occurring in 26% of patients. In conclusion, Apomine, at the current dose studied, failed to produce a 30% progression free survival rate at 16 weeks considered to be a meaningful benefit for further development.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Diphosphonates; Female; Humans; Male; Melanoma; Middle Aged
PubMed: 16379038
DOI: 10.1007/s10637-005-4544-y -
Cancer Feb 2012Osteosarcoma is the most frequent malignant primary bone tumor that occurs mainly in the young, with an incidence peak observed at age 18 years. Both apomine and...
BACKGROUND
Osteosarcoma is the most frequent malignant primary bone tumor that occurs mainly in the young, with an incidence peak observed at age 18 years. Both apomine and lovastatin have antitumor activity in a variety of cancer cell lines. Apomine, a 1,1-bisphosphonate-ester, increases the rate of degradation of 3-hydroxy-3 methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the mevalonate pathway, whereas lovastatin competitively inhibits HMG-CoA reductase enzyme activity, thereby preventing protein prenylation and cholesterol synthesis.
METHODS
The authors of this report investigated the effect of combined treatment with apomine and lovastatin in vitro on human and murine osteosarcoma cell lines and in vivo using a murine syngeneic model of osteosarcoma. Apomine and lovastatin synergistically decreased viability and induced apoptosis in both murine and human osteosarcoma cell lines.
RESULTS
Combined apomine and lovastatin strongly decreased HMG-CoA reductase enzyme levels compared with lovastatin treatment alone. Consequently, the accumulation of unprenylated ras-related protein 1A induced by lovastatin was enhanced in the presence of apomine. All synergistic effects on cell viability, apoptosis, and protein prenylation were overcome by the addition of mevalonate or geranylgeraniol, 2 mevalonate pathway intermediates downstream from the target enzyme, HMG-CoA reductase. This confirmed that the mechanism of synergy in osteosarcoma cells is through augmented inhibition of HMG-CoA reductase. Finally, treatment of POS-1 osteosarcoma-bearing mice with a combination of apomine and lovastatin significantly reduced tumor progression in these mice compared with single treatments, which had no effect at the doses used.
CONCLUSIONS
The results from this study revealed that combination therapy with apomine and lovastatin may be a novel treatment strategy for osteosarcoma.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bone Neoplasms; Cell Cycle; Cell Proliferation; Diphosphonates; Drug Synergism; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin; Male; Mice; Mice, Inbred C3H; Osteosarcoma; Protein Prenylation; Rats; Tumor Cells, Cultured
PubMed: 21751201
DOI: 10.1002/cncr.26336 -
Methods and Findings in Experimental... Sep 2006Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved... (Review)
Review
Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com This issue focuses on the following selection of drugs: A-007, A6, adalimumab, adenosine triphosphate, alefacept, alemtuzumab, AllerVax Ragweed, amphora, anakinra, angiotensin-(1-7), anidulafungin, apomine, aripiprazole, atomoxetine hydrochloride, avanafil; BAL-8557, becatecarin, bevacizumab, biphasic insulin aspart, BMS-188797, bortezomib, bosentan, botulinum toxin type B, brivudine; Calcipotriol/betamethasone dipropionate, caspofungin acetate, catumaxomab, certolizumab pegol, cetuximab, CG-0070, ciclesonide, cinacalcet hydrochloride, clindamycin phosphate/benzoyl peroxide, cryptophycin 52, Cypher; Dabigatran etexilate, darapladib, darbepoetin alfa, decitabine, deferasirox, desloratadine, dexanabinol, dextromethorphan/quinidine sulfate, DMF, drotrecogin alfa (activated), duloxetine hydrochloride; E-7010, edaravone, efalizumab, emtricitabine, entecavir, eplerenone, erlotinib hydrochloride, escitalopram oxalate, estradiol valerate/dienogest, eszopiclone, exenatide, ezetimibe; Fondaparinux sodium, fulvestrant; Gefitinib, gestodene, GYKI-16084; Hyaluronic acid, hydralazine hydrochloride/isosorbide dinitrate; Imatinib mesylate, indiplon, insulin glargine; Juzen-taiho-to; Lamivudine/zidovudine/abacavir sulfate, L-arginine hydrochloride, lasofoxifene tartrate, L-BLP-25, lenalidomide, levocetirizine, levodopa/carbidopa/entacapone, lexatumumab, lidocaine/prilocaine, lubiprostone, lumiracoxib; MAb-14.18, mitoquidone; Natalizumab, neridronic acid, neuradiab; Olpadronic acid sodium salt, omalizumab; p53-DC vaccine, parathyroid hormone (human recombinant), peginterferon alfa-2a, peginterferon alfa-2b, pemetrexed disodium, perifosine, pimecrolimus, prasterone, prasugrel, PRO-2000, Pseudostat; R24, rasburicase, RHAMM R3 peptide, rilonacept, rosuvastatin calcium, rotavirus vaccine, rufinamide; Sabarubicin hydrochloride, SHL-749, sirolimus-eluting stent, SLx-2101, sodium butyrate, sorafenib, SU-6668; TachoSil, tadalafil, taxus, tegaserod maleate, telbivudine, tenofovir disoproxil fumarate, teriparatide, tetramethylpyrazine, teverelix, tiotropium bromide, tipifarnib, tirapazamine, tolvaptan, TransvaxTM hepatitis C vaccine, treprostinil sodium; Valganciclovir hydrochloride, valsartan/amlodipine, vandetanib, vardenafil hydrochloride hydrate, vatalanib succinate, veglin, voriconazole; Yttrium 90 (90Y) ibritumomab tiuxetan; Zileuton, zotarolimus, zotarolimus-eluting stent.
Topics: Clinical Trials as Topic; Combined Modality Therapy; Drug Therapy; Humans; Treatment Outcome
PubMed: 17003851
DOI: No ID Found -
British Journal of Clinical Pharmacology Aug 20041) To characterize the population pharmacokinetics of apomine in healthy males and in male and female patients with solid tumours and 2) to understand more fully the... (Meta-Analysis)
Meta-Analysis
AIMS
1) To characterize the population pharmacokinetics of apomine in healthy males and in male and female patients with solid tumours and 2) to understand more fully the influence of induction and between- and within-subject variability on exposure to drug using Monte Carlo simulation.
METHODS
Apomine was administered once- or twice-daily with or without food in single and multiple oral doses of 30-2100 mg to healthy males (n = 19) and patients with solid tumours (n = 19). The data were divided into model development and validation sets. Models were developed using standard population methods. These were the identification of an appropriate base model, calculation of the empirical Bayes estimates of the primary pharmacokinetic parameters, covariate screening, forward stepwise addition of covariates using the likelihood ratio test as a model selection criteria, and backwards elimination to obtain the final model. To study the influence of data from individual subjects, the model development dataset was subjected to the delete-1 jack-knife and the final model was fitted to each jack-knifed dataset. Principal components analysis of the jack-knifed matrix of model parameters identified two influential subjects who were removed from the dataset, and the final model contained data from the remaining subjects. Model validation was examined using goodness of fit statistics and relative error measures using independent datasets from cancer patients. The model provided a reasonable approximation to the pharmacokinetic measurements in the validation datasets. Computer simulations were undertaken to understand further the pharmacokinetics of apomine in otherwise healthy females, a population not yet studied.
RESULTS
Apomine pharmacokinetics were complex and consistent with a two-compartment model with a lag-time. Apparent oral clearance at baseline and apparent volume of distribution at steady-state were larger in healthy males than in cancer patients (41 ml h(-1) and 14.1 l vs 10 ml h(-1) and 8.9 l, respectively, for a 75 kg person). Clearance was time-variant showing a maximal increase with full induction of 320 ml h(-1), independent of patient type. The time to reach 50% maximal induction was about 2 days. The fraction of drug absorbed was relatively constant at doses less than 100-200 mg once daily but decreased at higher doses. Food also decreased relative bioavailability by 36%. Patient characteristics had no effect on apomine pharmacokinetics except for weight, which was proportional to the volume of the central compartment. Between-subject variability (68% for clearance, 30% for central volume, and 141% for peripheral volume) was moderate to large and independent of patient type. Inter-occasion variability was small (18% for both clearance and central volume). Residual variability was modelled with an additive and proportional error model. Cancer patients had slightly higher plasma concentrations than healthy males but this difference was probably not clinically significant. Steady-state was reached in about 3-4 days after once-daily drug administration. The half-life of apomine after three weeks of once-daily dosing was 41 h in cancer patients and 32 h in healthy males.
CONCLUSIONS
A population model for apomine has been developed has been developed that characterizes its pharmacokinetics in cancer patients and healthy subjects under a variety of conditions.
Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Area Under Curve; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Diphosphonates; Female; Humans; Male; Middle Aged; Models, Chemical; Monte Carlo Method; Neoplasms
PubMed: 15255796
DOI: 10.1111/j.1365-2125.2004.02111.x -
International Journal of Pharmaceutics Dec 2009Apomine is a novel compound that inhibits the mevalonate/isoprenoid pathway of cholesterol synthesis and may prove effective as a skin cancer chemoprevention therapy....
Apomine is a novel compound that inhibits the mevalonate/isoprenoid pathway of cholesterol synthesis and may prove effective as a skin cancer chemoprevention therapy. This research was focused on the development of a new delivery approach for chemoprevention of melanoma using topically delivered apomine. This included evaluating the effect of several factors on the stability of apomine in solution, utilizing these to develop a topical formulation, and conducting efficacy studies with the developed topical formulation in the TPras mouse model. Preformulation included the influence of pH, buffer species, ionic strength, and organic solvents on the stability of apomine at four different temperatures. Apomine was determined to undergo apparent first-order degradation kinetics for all conditions evaluated. Apomine undergoes base-catalyzed degradation. Less than 15% degradation is observed after >200 days under acidic conditions. Long-term stability studies were performed on two different topical cream formulations and indicate that both formulations are chemically stable for over 1 year at both 4 and 23 degrees C. The efficacy of topically applied apomine, from ethanol and developed 1% cream, was evaluated in vivo against the incidence of melanoma. Regardless of delivery vehicle apomine treatment caused a significant reduction in tumor incidence. Ethyl alcohol application of apomine resulted in a greater tumor incidence reduction when compared to the development cream formulation; however, this difference was not significant.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Topical; Animals; Anticarcinogenic Agents; Buffers; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Diphosphonates; Drug Stability; Ethanol; Hydrogen-Ion Concentration; Kinetics; Melanoma, Experimental; Mice; Ointments; Osmolar Concentration; Skin Neoplasms; Solubility; Solvents; Technology, Pharmaceutical; Temperature; ras Proteins
PubMed: 19699284
DOI: 10.1016/j.ijpharm.2009.08.016 -
Biochemical and Biophysical Research... Apr 2000Apomine (SR-45023A) is a new antineoplastic compound which is currently in clinical trials and representative of the family of cholesterol synthesis inhibitors... (Comparative Study)
Comparative Study
Apomine (SR-45023A) is a new antineoplastic compound which is currently in clinical trials and representative of the family of cholesterol synthesis inhibitors 1,1-bisphosphonate esters. Apomine inhibits growth of a wide variety of tumor cell lines with IC(50) values ranging from 5 to 14 microM. The antiproliferative activity of apomine was studied in comparison with that of other inhibitors of the mevalonate/isoprenoid pathway of cholesterol synthesis, simvastatin, farnesol, and 25-hydroxycholesterol. All these compounds inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity. Apomine (IC(50) = 14 microM), simvastatin (IC(50) = 3 microM), farnesol (IC(50) = 60 microM), and 25-hydroxycholesterol (IC(50) = 2 microM) inhibited HL60 cell growth. Growth inhibition due to simvastatin was reverted by mevalonate, whereas the antiproliferative activity of apomine, farnesol, and 25-hydroxycholesterol was not. Apomine triggered apoptosis in HL60 cells in less than 2 h. Apomine and farnesol induced caspase-3 activity at concentrations similar to their IC(50) values for cell proliferation, whereas a 10-fold excess of simvastatin was necessary to trigger apoptosis compared to its potency on proliferation. Caspase-3 activity was not induced by 25-hydroxycholesterol. The overall similar profile on mevalonate synthesis inhibition, cell growth inhibition, and apoptosis suggests that apomine acts as a synthetic mimetic of farnesol.
Topics: Anticholesteremic Agents; Antineoplastic Agents; Apoptosis; Cell Division; Diphosphonates; Dose-Response Relationship, Drug; Farnesol; Humans; Hydroxycholesterols; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mevalonic Acid; Molecular Mimicry; Simvastatin; Terpenes; Tumor Cells, Cultured
PubMed: 10733934
DOI: 10.1006/bbrc.2000.2421