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Liposomes composed of a rigid bilayer have high plasma stability; however, they can be challenged in efficacy due to complications in releasing the encapsulated drug as well as being internalized by the tumor cell. On the other hand, fusogenic liposomes may fuse with the plasmatic membrane and release encapsulated material directly into the cytoplasm. In a previous study, fusogenic liposomes composed of alpha-tocopheryl succinate (TS) and doxorubicin (DOX) were developed (pHSL-TS-DOX). These stabilized tumor growth and reduced toxicity compared to a commercial formulation. In the present study, we investigated whether cellular uptake or DOX accumulation in the tumor could justify the better performance of the pHSL-TS-DOX formulation. Release, deformability, and DOX plasmatic concentration studies were also carried out. pHSL-TS-DOX showed an adequate release profile and demonstrated characteristics of a deformable formulation. Data from apoptosis, cell cycle, and nuclear morphology studies have shown that the induction of cell death caused by pHSL-TS-DOX occurred more quickly. Higher DOX cellular uptake and tumor accumulation were observed when pHSL-TS-DOX was administered, demonstrating better drug delivery capacity. Therefore, better DOX uptake as well as tumor accumulation explain the great antitumor activity previously demonstrated for this formulation.

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The discovery of alpha-tocopheryl succinate (alpha-TS) as a cancer therapeutic agent markedly stimulated research with or without tumor therapeutic agents on cancer cells and normal cells. Results showed that alpha-TS treatment induced apoptosis in cancer cells and enhanced the apoptotic effects of tumor therapeutic agents on tumor cells in a synergistic manner without affecting the growth of normal cells. Liposomal alpha-TS was more effective than alpha-TS. Some tumors are difficult to treat with chemotherapeutic agents while some become resistant of such treatment. Using a nanotechnology technique, it was demonstrated that alpha-TS conjugated with a chemotherapeutic agent enhanced the levels of apoptosis and restored the sensitivity of tumor cells to that chemotherapeutic agent. The mechanisms of action of alpha-TS alone or in combination with therapeutic agents include the following: (a) inhibition of the expression of oncogenes C-myc and H-ras; (b) alterations in the levels of expression of numerous genes; (c) activation of caspases; (d) inhibition of angiogenesis; (e) destabilization of mitochondria and lysosomes; (f) inhibition of production of production of prostaglandin E2 (PGE2) and PGE2-mediated pro-inflammatory responses; (g) reduction of survivin signaling pathway; and (h) reduction of CD47 expression on the tumor cell surface causing enhancement of phagocytic activity of macrophages leading to engulfment of tumor cells. Despite impressive results in cell culture and in animal models, no studies with alpha-TS alone or in combination with cancer therapeutic agents in human cancer resistant to these therapies have been performed.

Alpha-TS inhibited the growth of cancer cells without affecting normal cells.Alpha-TS enhanced the effects of therapeutic agents on tumor cells but not on normal cells.Liposomal alpha-TS was more effective than alpha-TS.Using a nanotechnology technique, alpha-TS conjugated with a chemotherapeutic agent produced synergistic growth inhibition in cancer cells but not in normal cells.

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BACKGROUND/AIM: This study analysed the effect of α-tocopheryl succinate (α-TS) on the redox-state of leukemia and normal lymphocytes, as well as their sensitization to fifteen anticancer drugs. MATERIALS AND METHODS: Cell viability was analyzed by trypan blue staining and automated counting of live and dead cells. Apoptosis was analyzed by FITC-Annexin V test. Oxidative stress was evaluated by the intracellular levels of reactive oxygen species (ROS) and protein-carbonyl products. RESULTS: Most combinations (α-TS plus anticancer drug) exerted additive or antagonistic effects on the proliferation and viability of leukemia lymphocytes. α-TS combined with barasertib, bortezomib or lonafarnib showed a strong synergistic cytotoxic effect, which was best expressed in the case of barasestib. It was accompanied by impressive induction of apoptosis and increased production of ROS, but insignificant changes in protein-carbonyl levels. α-TS plus barasertib did not alter the viability and did not induce oxidative stress and apoptosis in normal lymphocytes. CONCLUSION: α-TS could be a promising adjuvant in second-line anticancer therapy, particularly in acute lymphoblastic leukemia, to reduce the therapeutic doses of barasertib, bortezomib, and lonafarnib, increasing their effectiveness and minimizing their side effects.

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Abundant reactive oxygen species and tumor necrosis factor-α (TNF-α) cytokine supply of M1-type macrophages boost rheumatoid arthritis (RA) pathological process. For efficient RA therapy, here a multifunctional nanoplatform is presented based on generation 5 (G5) poly(amidoamine) dendrimer-entrapped gold nanoparticles (Au DENPs) to achieve co-delivery of antioxidant alpha-tocopheryl succinate (α-TOS) and anti-inflammatory anti-TNF-α siRNA to macrophage cells. G5 dendrimers with amine termini are sequentially functionalized with 1,3-propane sultone (1,3-PS), α-TOS through a polyethylene glycol (PEG) spacer, and PEGylated folic acid (FA), and subsequently entrapped with Au NPs. The generated functional Au DENPs exhibit desired cytocompatibility, zwitterion-rendered antifouling property, and FA-mediated targeting specificity, enabling serum-enhanced siRNA delivery to M1-type macrophage cells. Meanwhile, the attached α-TOS affords enhanced oxidation resistance of macrophage cells. In vivo investigation shows that the treatment of a collagen-induced arthritis mouse model using α-TOS-modified Au DENPs/TNF-α siRNA polyplexes can achieve excellent combination therapy effect in inflammatory cytokines downregulation of RA lesion and bone erosions. The therapeutic efficacy is also supported by 3D micro-computed tomography analysis and TNF-α cytokine reduction of RA lesion joints in the mRNA, protein, and histology levels. The created multifunctional nanoplatform may be employed in antioxidative and anti-inflammatory combination therapy of RA.

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Pancreatic cancer is one of the highest causes of mortality throughout the world; thus, it requires an effective treatment strategy. Some chemotherapeutic agents used in the clinics or under clinical trials are hydrophobic and have poor aqueous solubility; consequently, they also have minimal systemic bioavailability. Nanoparticle-based drug delivery tactics have the potential for overcoming these limitations and enhancing their therapeutic efficacy. Herein, a glutathione (GSH)-sensitive micelle (PAH-SS-PLGA) was synthesized for the combined delivery of alpha-tocopheryl succinate (TOS) and curcumin to improve its therapeutic efficacy. The chemical structures of PAH-SS-PLGA were analyzed using Proton Nuclear Magnetic Resonance (1H-NMR) and Fourier Transform Infrared (FTIR) spectroscopy, whereas the particle size, zeta potential, and surface morphology were observed using dynamic light scattering (DLS) and transmission electron microscopy (TEM). In vitro drug release results revealed that more TOS and curcumin were released in the presence of GSH (5 mM) than the physiological pH value. Fluorescence microscopy images revealed that nanoformulated curcumin/rhodamine was uptaken by PAN02 pancreatic cancer cells. In vitro cytotoxicity assays showed higher cytotoxicity for nanoformulated TOS and/or curcumin than free TOS and/or curcumin. In addition, higher cytotoxicity was observed for combination drugs than free drugs alone. Most interestingly, at all tested concentrations of nanoformulated drugs (PAH-SS-PLGA, TOS, and curcumin), the calculated combination index (CI) value was less than one, which shows that TOS and curcumin have a synergistic effect on cellular proliferation inhibition. Overall, synthesized co-polymers are the best carriers for combination drugs, TOS, and curcumin, because they enhance the therapeutic efficacy and improve pancreatic cancer treatments.

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The downregulation of the denitrosylating enzyme S-nitrosoglutathione reductase (GSNOR, EC:1.1.1.284), is a feature of hepatocellular carcinoma (HCC). This condition causes mitochondrial rearrangements that sensitize these tumors to mitochondrial toxins, in particular to the mitochondrial complex II inhibitor alpha-tocopheryl succinate (αTOS). It has also been reported the GSNOR depletion impairs the selective degradation of mitochondria through mitophagy; however, if this contributes to GSNOR-deficient HCC cell sensitivity to αTOS and can be applied to anticancer therapies, is still not known. Here, we provide evidence that GSNOR-deficient HCC cells show defective mitophagy which contributes to αTOS toxicity. Mitophagy inhibition by Parkin (EC: 2.3.2.31) depletion enhances αTOS anticancer effects, thus suggesting that this drug could be effective in treating mitophagy-defective tumors.

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Doxorubicin (DOX) plays an important role in cancer treatment; however, high cardiotoxicity and low penetration in solid tumors are the main limitations of its use. Liposomal formulations have been developed to attenuate the DOX toxicity, but the technological enhancement of the liposomal formulation as well as the addition of another agent with antitumor properties, like alpha-tocopheryl succinate (TS), a semi-synthetic analog of vitamin E, could certainly bring benefits. Thus, in this study, it was proposed the development of liposomes composed of DOX and TS (pHSL-TS-DOX). A new DOX encapsulation method, without using the classic ammonium sulfate gradient with high encapsulation percentage was developed. Analysis of Small Angle X-ray Scattering (SAXS) and release study proved the pH-sensitivity of the developed formulation. It was observed stabilization of tumor growth using pHSL-TS-DOX when compared to free DOX. The toxicity tests showed the safety of this formulation since it allowed body weight initial recovery after the treatment and harmless to heart and liver, main target organs of DOX toxicity. The developed formulation also avoided the occurrence of myelosuppression, a typical adverse effect of DOX. Therefore, pHSL-TS-DOX is a promising alternative for the treatment of breast cancer since it has adequate antitumor activity and a safe toxicity profile.

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Mitochondrial targeting is a promising approach for solving current issues in clinical application of chemotherapy and diagnosis of several disorders. Here, we discuss direct conjugation of mitochondrial-targeting moieties to anticancer drugs, antioxidants and sensor molecules. Among them, the most widely applied mitochondrial targeting moiety is triphenylphosphonium (TPP), which is a delocalized cationic lipid that readily accumulates and penetrates through the mitochondrial membrane due to the highly negative mitochondrial membrane potential. Other moieties, including short peptides, dequalinium, guanidine, rhodamine, and F16, are also known to be promising mitochondrial targeting agents. Direct conjugation of mitochondrial targeting moieties to anticancer drugs, antioxidants and sensors results in increased cytotoxicity, anti-oxidizing activity and sensing activity, respectively, compared with their non-targeting counterparts, especially in drug-resistant cells. Although many mitochondria-targeted anticancer drug conjugates have been investigated in vitro and in vivo, further clinical studies are still needed. On the other hand, several mitochondria-targeting antioxidants have been analyzed in clinical phases I, II and III trials, and one conjugate has been approved for treating eye disease in Russia. There are numerous ongoing studies of mitochondria-targeted sensors.

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This study investigates the impact of the chemical nature of lipids and additive on the formulation and properties of pH sensitive liposomes. The objective is to understand the respective role of the formulation parameters on the liposome properties in order to optimize the conditions for efficient encapsulation of doxorubicin (DOX). These liposomes should be stable at physiological pH, and disrupt in slightly acidic media such as the tumor microenvironment to release their DOX load. The major challenge for encapsulating DOX in pH sensitive liposomes lies in the fact that this drug is soluble at low pH (when the pH-sensitive liposomes are not stable), but the DOX aqueous solubility decreases in the pH conditions corresponding to the stability of the pH-sensitive liposomes. The study of pH-sensitivity of liposomes was conducted using carboxyfluorescein (CF) encapsulated in high concentration, i.e. quenched, and following the dye dequenching as sensor of the liposome integrity. We studied the impact of (i) the chemical nature of lipids (dioleoyl phosphatidyl ethanolamine (DOPE), palmitoyl-oleoyl phosphatidyl ethanolamine (POPE) and dimyristoyl phosphatidyl ethanolamine (DMPE)) and (ii) the lipid/stabilizing agent ratio (alpha-tocopheryl succinate), on the pH sensitivity of the liposomes. Optimized liposome formulations were then selected for the encapsulation of DOX by an active loading procedure, i.e. driven by a difference in pH inside and outside the liposomes. Numerous experimental conditions were explored, in function of the pH gradient and liposome composition, which allowed identifying critical parameters for the efficient DOX encapsulation in pH-sensitive liposomes.

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α-Tocopheryl succinate (α-TOS), a derivative of vitamin E, is synthesized by esterification of α-tocopherol. It has been reported that α-TOS inhibits the mitochondrial complex II resulting in generation of reactive oxygen species, which triggers selective apoptosis in a large number of cancer cells, while it appears largely non-toxic towards normal cells. Plasmodium parasites are well known to have high sensitivity to oxidative stress. Thus, α-TOS is suspected to impact Plasmodium parasites by oxidative stress. In this study, to ascertain whether α-TOS is an appropriate candidate for an anti-malarial drug, C57BL/6J mice were infected with P. yoelii 17XL and P. berghei ANKA, a lethal strain of rodent malaria and experimental cerebral malaria (ECM), and treated with several concentrations of α-TOS by intraperitoneal administration on 1, 3, 5, and 7 days post infection (dpi). In addition, the permeability of the blood brain barrier (BBB) was examined by Evans blue staining in ECM on 7 dpi. As a result of α-TOS treatment, parasitemia was decreased and survival rate was significantly increased in mice infected with both parasites. Furthermore, the intensity of Evans blue staining on brains taken from α-TOS-treated mice was weaker than that of untreated mice. This means that α-TOS might inhibit the breakdown of BBB and progress of cerebral malaria. These findings indicate that vitamin E derivatives like α-TOS might be a potential candidate for treatment drugs against malaria.

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BACKGROUND: Breast cancer is one of the most common cancers affecting women and has a high incidence of bone metastasis, causing osteolytic lesions. The elevated expression of receptor activator of nuclear factor-κB ligand (RANKL) in cancer activates osteoclasts, leading to bone destruction. We previously reported that α-tocopheryl succinate (αTP-suc) inhibited interleukin-1-induced RANKL expression in osteoblasts. Here, we examined the effect of αTP-suc on osteolytic bone metastasis in breast cancer. METHODS: To examine the effect of αTP-suc on the metastatic capacity of breast cancer, MDA-MB-231-FL cells were injected into the left cardiac ventricle of BALB/c nude mice along with intraperitoneal injection of αTP-suc. The mice were then analyzed by bioluminescence imaging. To investigate the effect of αTP-suc on osteolysis, 4T1 cells were directly injected into the femur of BALB/c mice along with intraperitoneal injection of αTP-suc. Microcomputed tomography analysis and histomorphometric analysis of the femora were performed. RESULTS: αTP-suc inhibited cell migration and cell growth of 4T1 cells. In line with these results, bone metastasis of MDA-MB-231-FL cells was reduced in mice injected with αTP-suc. In addition, αTP-suc decreased osteoclastogenesis by inhibiting 4T1-induced RANKL expression in osteoblasts. Consistent with these results, 4T1-induced bone destruction was ameliorated by αTP-suc, with in vivo analysis showing reduced tumor burden and osteoclast numbers. CONCLUSIONS: Our findings suggest that αTP-suc may be efficiently utilized to prevent and treat osteolytic bone metastasis of breast cancer with dual effects.

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BACKGROUND: Breast cancer is one of the most common cancers affecting women and has a high incidence of bone metastasis, causing osteolytic lesions. The elevated expression of receptor activator of nuclear factor-κB ligand (RANKL) in cancer activates osteoclasts, leading to bone destruction. We previously reported that α-tocopheryl succinate (αTP-suc) inhibited interleukin-1-induced RANKL expression in osteoblasts. Here, we examined the effect of αTP-suc on osteolytic bone metastasis in breast cancer. METHODS: To examine the effect of αTP-suc on the metastatic capacity of breast cancer, MDA-MB-231-FL cells were injected into the left cardiac ventricle of BALB/c nude mice along with intraperitoneal injection of αTP-suc. The mice were then analyzed by bioluminescence imaging. To investigate the effect of αTP-suc on osteolysis, 4T1 cells were directly injected into the femur of BALB/c mice along with intraperitoneal injection of αTP-suc. Microcomputed tomography analysis and histomorphometric analysis of the femora were performed. RESULTS: αTP-suc inhibited cell migration and cell growth of 4T1 cells. In line with these results, bone metastasis of MDA-MB-231-FL cells was reduced in mice injected with αTP-suc. In addition, αTP-suc decreased osteoclastogenesis by inhibiting 4T1-induced RANKL expression in osteoblasts. Consistent with these results, 4T1-induced bone destruction was ameliorated by αTP-suc, with in vivo analysis showing reduced tumor burden and osteoclast numbers. CONCLUSIONS: Our findings suggest that αTP-suc may be efficiently utilized to prevent and treat osteolytic bone metastasis of breast cancer with dual effects.

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Ulcerative colitis (UC) is a severe inflammatory disease in colon, however, the therapeutic efficacy of the standard-of-care in clinic for UC patients is unsatisfactory. To explore new drugs for effective and safe treatment of UC, alpha-tocopheryl succinate (α-TOS) is conjugated to generation 5 (G5) poly(amidoamine) (PAMAM) dendrimer to construct a nanodevice of G5-NH-acetamide (Ac)-TOS. The inhibitory effects of the G5-NH-Ac-TOS on UC are evaluated in vivo in a dextran sulfate sodium induced UC mouse model, and its mechanisms are explored in vitro in lipopolysaccharide stimulated mouse peritoneal macrophages. The results indicate that the G5-NH-Ac-TOS exhibits greater inhibitive effects on UC than free α-TOS, through significant attenuation of the disease activity index and reduction of macrophage infiltration in the colon tissues. The protective mechanisms of the G5-NH-Ac-TOS are revealed to be related to inhibition of expression of nuclear translocation of NF-κB, phosphorylation of Akt, and reduction of reactive oxygen species production in the macrophages.

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We report here the synthesis of multifunctional dendrimer-entrapped gold nanoparticles (Au DENPs) modified with alpha-tocopheryl succinate (α-TOS) and arginine-glycine-aspartic acid (RGD) peptide for targeted chemotherapy and computed tomography (CT) imaging of cancer cells. In this work, generation 5 poly(amidoamine) dendrimers pre-conjugated with fluorescein isothiocyanate (FI), RGD peptide via a polyethylene glycol (PEG) spacer, and PEG-linked α-TOS were used as templates to synthesize AuNPs. Followed by acetylation of the remaining dendrimer terminal amines, multifunctional Au DENPs with an Au core size of 4.0nm were generated. The formed multifunctional Au DENPs were characterized via different techniques. We show that the multifunctional Au DENPs are stable at different pH (5-8) and temperature (4-50°C) conditions and display enhanced efficacy in the generation of reactive oxygen species, which is associated with their increased ability to induce apoptosis. Thanks to the role played by RGD-mediated targeting, the multifunctional Au DENPs are able to target cancer cells overexpressing αvß3 integrin and specifically inhibit the growth of the cancer cells. Likewise, the existence of AuNPs enabled the multifunctional Au DENPs to have a better X-ray attenuation property than clinically used iodinated CT contrast agents (e.g., Omnipaque) and the use of them as a nanoprobe for targeted CT imaging of cancer cells in vitro. The formed multifunctional Au DENPs may hold great promise to be used as a theranostic platform for cancer theranostics.

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Pro-apoptotic analogues of vitamin E (VE) exert selective anti-cancer effect on various animal cancer models. Neither suitable formulation of α-tocopheryl succinate (α-TOS), representative semi-synthetic VE analogue ester, nor suitable formulations of the other VE analogues for clinical application have been reported yet. The major factor limiting the use of VE analogues is their low solubility in aqueous solvents. Due to the hydrophobic character of VE analogues, liposomes are predetermined as suitable delivery system. Liposomal formulation prevents undesirable side effects of the drug, enhances the drug biocompatibility, and improves the drug therapeutic index. Liposomal formulations of VE analogues especially of α-TOS and α-tocopheryl ether linked acetic acid (α-TEA) have been developed. The anti-cancer effect of these liposomal VE analogues has been successfully demonstrated in pre-clinical models in vivo. Present achievements in: (i) preparation of liposomal formulations of VE analogues, (ii) physico-chemical characterization of these developed systems and (iii) testing of their biological activity such as induction of apoptosis and evaluation of anti-cancer effect are discussed in this review.

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Development of multifunctional theranostic nanoplatforms for targeted cancer imaging and therapy still remains a great challenge. Herein, we report the use of multifunctional dendrimer-entrapped gold nanoparticles (Au DENPs) covalently linked with α-tocopheryl succinate (α-TOS) as a platform for targeted cancer computed tomography (CT) imaging and therapy. In this study, amine-terminated poly(amidoamine) dendrimers of generation 5 (G5.NH2) conjugated with fluorescein isothiocyanate (FI), polyethylene glycol (PEG)-modified α-TOS, and PEGylated folic acid (FA) were used as templates to synthesize Au DENPs, followed by acetylation of the remaining dendrimer terminal amines. The formed multifunctional Au DENPs were characterized via different techniques. We show that the Au DENPs conjugated with approximately 9.8 α-TOS molecules per dendrimer and with an Au core size of 3.3 nm are water-dispersible, and stable under different pH and temperature conditions and in different aqueous media. The FA modification onto the Au DENPs enables efficient targeting of the particles to cancer cells overexpressing FA receptors (FAR), and effective targeted CT imaging of the cancer cells in vitro and the xenografted tumor model in vivo. Likewise, the covalent conjugation of α-TOS does not compromise its therapeutic activity, instead significantly improves its water solubility. Importantly, thanks to the role of FA-directed targeting, the formed multifunctional Au DENPs are able to exert the specific therapeutic efficacy of α-TOS to the FAR-overexpressing cancer cells in vitro and the xenografted tumor model in vivo. The developed multifunctional Au DENPs may hold a great promise to be used as a unique theranostic nanoplatform for targeted CT imaging and therapy of different types of cancer.

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OBJECTIVE: Osteoclasts are bone-resorbing multinucleated cells derived from the monocyte/macrophage lineage during normal and pathological bone turnover. Recently, several studies revealed that alpha-tocopheryl succinate (αTP-suc) have demonstrated potent anti-cancer activities in vitro and in vivo. However, the effects of αTP-suc on osteoclast formation and bone resorption remain unknown. Thus, in this study, we examined the effects of αTP-suc on osteoclast differentiation and bone resorbing activity in inflammatory bone loss model. METHODS: Osteoclast differentiation assay was performed by cocultures of mouse bone marrow cells and calvarial osteoblasts in culture media including interleukin-1 (IL-1). Osteoclasts were stained for tartrate-resistant acid phosphatase (TRAP). The level of receptor activator of nuclear factor-kappaB ligand (RANKL) mRNA was determined by reverse transcriptase-polymerase chain reaction (RT-PCR). ICR mice were administered an intraperitoneal injections of αTP-suc or dimethyl sulfoxide (DMSO) 1 day before the implantation of a freeze-dried collagen sponge loaded with phosphate-buffered saline (PBS) or IL-1 over the calvariae and every other day for 7 days. The whole calvariae were obtained and analyzed by micro-computed tomography (CT) scanning, and stained for TRAP. RESULTS: αTP-suc inhibits osteoclast formation in cocultures stimulated by IL-1 and decreased the level of expression of RANKL mRNA in osteoblasts. In addition, administered intraperitoneal injections of αTP-suc prevented IL-1-mediated osteoclast formation and bone loss in vivo. CONCLUSION: Our findings suggest that αTP-suc may have therapeutic value for treating and preventing bone-resorptive diseases, such as osteoporosis.

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OBJECTIVE: Osteoclasts are bone-resorbing multinucleated cells derived from the monocyte/macrophage lineage during normal and pathological bone turnover. Recently, several studies revealed that alpha-tocopheryl succinate (alphaTP-suc) have demonstrated potent anti-cancer activities in vitro and in vivo. However, the effects of alphaTP-suc on osteoclast formation and bone resorption remain unknown. Thus, in this study, we examined the effects of alphaTP-suc on osteoclast differentiation and bone resorbing activity in inflammatory bone loss model. METHODS: Osteoclast differentiation assay was performed by cocultures of mouse bone marrow cells and calvarial osteoblasts in culture media including interleukin-1 (IL-1). Osteoclasts were stained for tartrate-resistant acid phosphatase (TRAP). The level of receptor activator of nuclear factor-kappaB ligand (RANKL) mRNA was determined by reverse transcriptase-polymerase chain reaction (RT-PCR). ICR mice were administered an intraperitoneal injections of alphaTP-suc or dimethyl sulfoxide (DMSO) 1 day before the implantation of a freeze-dried collagen sponge loaded with phosphate-buffered saline (PBS) or IL-1 over the calvariae and every other day for 7 days. The whole calvariae were obtained and analyzed by micro-computed tomography (CT) scanning, and stained for TRAP. RESULTS: alphaTP-suc inhibits osteoclast formation in cocultures stimulated by IL-1 and decreased the level of expression of RANKL mRNA in osteoblasts. In addition, administered intraperitoneal injections of alphaTP-suc prevented IL-1-mediated osteoclast formation and bone loss in vivo. CONCLUSION: Our findings suggest that alphaTP-suc may have therapeutic value for treating and preventing bone-resorptive diseases, such as osteoporosis.

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