Comparison of a Novel Homogeneous Cyclic Amp Assay and a Luciferase Assay for Measuring Stimulating Thyrotropin-Receptor Autoantibodies

Objective: Stimulating thyrotropin-receptor antibodies (TSAb) cause Graves’ disease (GD). We tested a novel homogeneous fluorescent 3′,5′ cyclic adenine monophosphate (cAMP) assay for the detection of TSAb in a bioassay. Methods: Chinese hamster ovary (CHO) cell lines expressing either a chimeric (MC4) or wild-type (WT) TSH-R were incubated with the adenyl cyclase activator forskolin, a human TSAb monoclonal antibody (M22), and with sera from GD patients. Intracellular cAMP levels were measured using a Bridge-It® cAMP assay, and the results were compared with a luciferase-based bioassay. Results: Both cell lines were stimulated with forskolin concentrations (0.006–200 µM) in a dose-dependent manner. The linear range in the MC4 and WT cells was 0.8–25 and 3.1–50 µM, respectively. Levels of cAMP and luciferase in forskolin-treated MC4 and WT cells were positively correlated (r = 0.91 and 0.84, both p < 0.001). The 50% maximum stimulatory concentration of forskolin was more than 16-fold higher for the CHO-WT cells than the CHO-MC4 cells in the cAMP assay and 4-fold higher in the luciferase assay. Incubation of both cell lines with M22 (0.006–50 ng/mL) resulted in a dose-dependent increase in cAMP levels with linear ranges for the MC4 and WT cells of 0.8–12.5 and 0.2–3.125 ng/mL, respectively. Comparison of cAMP and luciferase levels in M22-treated MC4 and WT cells also showed a positive correlation (r = 0.88, p < 0.001 and 0.75, p = 0.002). A positive correlation was also noted when using patient samples (r = 0.96, p < 0.001) that were all TSH-R-Ab binding assay positive. Conclusion: The novel, rapid, simple-to-perform cAMP assay provides TSAb-mediated stimulatory results comparable to a luciferase-based bioassay.

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Role Of Cyclic Amp In The Inhibition Of Human Platelet Functions By Quercetin, A Flav0N0Id That Potentiates PGI2 Effect

10.1055/s-0038-1652487 ◽

1981 ◽

Author(s):

J P Cazenave ◽

A Beretz ◽

A Stierlé ◽

R Anton

Keyword(s):

Maximum Level ◽

Inhibitory Effect ◽

Dependent Manner ◽

Pde Inhibitors ◽

Pde Inhibition ◽

Induced Aggregation ◽

Camp Levels ◽

Dose Dependent

Injury to the endothelium (END) and subsequent platelet (PLAT)interactions with the subEND are important steps in thrombosis and atherosclerosis. Thus,drugs that protect the END from injury and also inhibit PLAT function are of interest. It has been shown that some flavonoids(FLA), a group of compounds found in plants, prevent END desquamation in vivo, inhibit cyclic nucleotide phosphodiesterases(PDE)and inhibit PLAT function. We have studied the structure-activity relationships of 13 purified FLA on aggregation and secretion of 14c-5HT of prelabeled washed human PLAT induced by ADP, collagen(COLL) and thrombin(THR). All the FLA were inhibitors of the 3 agents tested. Quercetin(Q), was the second best after fisetin. It inhibited secretion and aggregation with I50 of 330µM against 0.1 U/ML.THR, 102µM against 5µM ADP and 40 µM against COLL. This inhibitory effect is in the range of that of other PDE inhibitors like dipyridamole or 3-isobutyl-l- methylxanthine. The aggregation induced by ADP, COLL and THR is at least mediated by 3 mechanisms that can be inhibited by increasing cAMP levels. We next investigated if Q, which is a PDE inhibitor of bovine aortic microsomes,raises PLAT cAMP levels. cAMP was measured by a protein-binding method. ADP- induced aggregation(5µM) was inhibited by PGI2 (0.1 and 0.5 nM) . Inhibition was further potentiated(l.7 and 3.3 times) by lOµM Q, which alone has no effect on aggregation. The basal level of cAMP(2.2 pmol/108PLAT) was not modified by Q (50 to 500µM). Using these concentrations of Q,the rise in cAMP caused by PGI2(0.1 and 0.5nM) was potentiated in a dose dependent manner. Q potentiated the effect of PGI2 on the maximum level of cAMP and retarded its breakdown. Thus Q and possibly other FLA could inhibit the interaction of PLAT with the components of the vessel wall by preventing END damage and by inhibiting PLAT function through a rise in cAMP secondary to PDE inhibition and potentiation of the effect of vascular PGI2 on PLAT adenylate cyclase.

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Kahweol Exerts Skin Moisturizing Activities by Upregulating STAT1 Activity

International Journal of Molecular Sciences ◽

10.3390/ijms22168864 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8864

Author(s):

Hongxi Chen ◽

Mohammad Amjad Hossain ◽

Jong-Hoon Kim ◽

Jae Youl Cho

Keyword(s):

Proper Time ◽

Radical Scavenging ◽

Polymerase Chain Reaction Analysis ◽

Luciferase Assay ◽

Dependent Manner ◽

Diphenyltetrazolium Bromide ◽

Polymerase Chain ◽

Radical Scavenging Ability ◽

The Relationship ◽

Dose Dependent

Kahweol is a diterpene present in coffee. Until now, several studies have shown that kahweol has anti-inflammatory and anti-angiogenic functions. Due to the limited research available about skin protection, this study aims to discern the potential abilities of kahweol and the possible regulation targets. First, the cytotoxicity of kahweol was checked by 3-4-5-dimethylthiazol-2-yl)-2-5-diphenyltetrazolium bromide assay, while 2,20-azino-bis (3ethylbenzothiazoline-6-sulphonic acid) diammonium salt and 1-diphenyl-2-picryl-hydrazyl were used to examine the radical scavenging ability. Polymerase chain reaction analysis was performed to explore the proper time points and doses affecting skin hydration and barrier-related genes. Luciferase assay and Western blotting were used to explore the possible transcription factors. Finally, fludarabine (a STAT1 inhibitor) was chosen to discern the relationship between skin-moisturizing factors and STAT1. We found that HaCaT cells experienced no toxicity from kahweol, and kahweol displayed moderate radical scavenging ability. Moreover, kahweol increased the outcome of HAS1, HAS2, occludin, and TGM-1 from six hours in a dose-dependent manner as well as the activation of STAT1 from six hours. Additionally, kahweol recovered the suppression of HAS2, STAT1-mediated luciferase activity, and HA secretion, which was all downregulated by fludarabine. In this study, we demonstrated that kahweol promotes skin-moisturizing activities by upregulating STAT1.

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Hif-1α Inhibitors Could Successfully Inhibit the Progression of Differentiated Thyroid Cancer in Vitro

Pharmaceuticals ◽

10.3390/ph13090208 ◽

2020 ◽

Vol 13 (9) ◽

pp. 208

Author(s):

Min-Hee Kim ◽

Tae Hyeong Lee ◽

Jin Soo Lee ◽

Dong-Jun Lim ◽

Peter Chang-Whan Lee

Keyword(s):

Cell Proliferation ◽

Thyroid Cancer ◽

Cell Lines ◽

Cancer Progression ◽

Hypoxia Inducible Factor ◽

Soft Agar ◽

Dependent Manner ◽

Thyroid Cancer Cell Lines ◽

Dose Dependent

Hypoxia-inducible factor (HIF)-1α plays an important role in cancer progression. In various cancers, including thyroid cancer, overexpression of HIF-1α is related to poor prognosis or treatment response. However, few studies have investigated the role of HIF-1α inhibition in thyroid cancer progression. We evaluated the utility of the HIF-1α inhibitor IDF-11774 in vitro utilizing two thyroid cancer cell lines, K1 and BCPAP. Both cell lines were tested to elucidate the effects of IDF-11774 on cell proliferation and migration using soft agar and invasion assays. Here, we found that a reduction of HIF-1α expression in BCPAP cells was observed after treatment with IDF-11774 in a dose-dependent manner. Moreover, cell proliferation, migration, and anchorage-independent growth were effectively inhibited by IDF-11774 in BCPAP cells but not in K1 cells. Additionally, invasion of BCPAP but not K1 cells was controlled with IDF-11774 in a dose-dependent manner. Our findings suggest that promoting the degradation of HIF-1α could be a strategy to manage progression and that HIF-1α inhibitors are potent drugs for thyroid cancer treatment.

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Anticancer Potential of Fruit Extracts from Vatica diospyroides Symington Type SS and Their Effect on Program Cell Death of Cervical Cancer Cell Lines

The Scientific World JOURNAL ◽

10.1155/2019/5491904 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9 ◽

Cited By ~ 4

Author(s):

Atchara Chothiphirat ◽

Kesara Nittayaboon ◽

Kanyanatt Kanokwiroon ◽

Theera Srisawat ◽

Raphatphorn Navakanitworakul

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Morphological Changes ◽

Annexin V ◽

Siha Cell ◽

Caspase 8 ◽

Dependent Manner ◽

Cervical Cancer Cells ◽

Dose Dependent

Vatica diospyroides Symington is locally known as Chan-Ka-Pho in Thailand. Ancient people have used it as therapeutic plant for cardiac and blood tonic cure. The purpose of this study was to investigate the potential cytotoxicity and selectivity of the extracts from V. diospyroides type SS fruit on cervical cancer HeLa and SiHa cell lines and to examine its underlying mechanism of action. MTT assay revealed that the extracts showed inhibition of cell survival in a dose-dependent manner and exhibited highly cytotoxic activity against both HeLa and SiHa cells with IC50 value less than 20 μg/mL along with less toxicity against L929 cells. Acetone cotyledon extract (ACE) showed the best selectivity index value of 4.47 (HeLa) and 3.51 (SiHa). Distinctive morphological changes were observed in ACE-treated cervical cancer cells contributing to apoptosis action. Flow cytometry analysis with Annexin V-FITC and PI staining precisely indicated that ACE induced apoptosis in HeLa and SiHa cell lines in a dose-dependent manner. Treatment of ACE with half IC50 caused DNA fragmentation and also activated increasing of bax and cleaved caspase-8 protein in HeLa cells after 48 h exposure. The results suggest that ACE has potent and selective cytotoxic effect against cervical cancer cells and the potential to induce bax and caspase-8-dependent apoptosis. Hence, the ACE could be further exploited as a potential lead in cancer treatment.

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Cyclic AMP-dependent Protein Lysine Acylation in Mycobacteria Regulates Fatty Acid and Propionate Metabolism

Journal of Biological Chemistry ◽

10.1074/jbc.m113.463992 ◽

2013 ◽

Vol 288 (20) ◽

pp. 14114-14124 ◽

Cited By ~ 69

Author(s):

Subhalaxmi Nambi ◽

Kallol Gupta ◽

Moitrayee Bhattacharyya ◽

Parvathy Ramakrishnan ◽

Vaishnavi Ravikumar ◽

...

Keyword(s):

Critical Role ◽

Fatty Acyl ◽

Intracellular Camp ◽

Dependent Manner ◽

Multiple Substrates ◽

Propionate Metabolism ◽

Lysine Residues ◽

Dependent Protein ◽

First Time ◽

Camp Levels

Acetylation of lysine residues is a posttranslational modification that is used by both eukaryotes and prokaryotes to regulate a variety of biological processes. Here we identify multiple substrates for the cAMP-dependent protein lysine acetyltransferase from Mycobacterium tuberculosis (KATmt). We demonstrate that a catalytically important lysine residue in a number of FadD (fatty acyl CoA synthetase) enzymes is acetylated by KATmt in a cAMP-dependent manner and that acetylation inhibits the activity of FadD enzymes. A sirtuin-like enzyme can deacetylate multiple FadDs, thus completing the regulatory cycle. Using a strain deleted for the KATmt ortholog in Mycobacterium bovis Bacillus Calmette-Guérin (BCG), we show for the first time that acetylation is dependent on intracellular cAMP levels. KATmt can utilize propionyl CoA as a substrate and, therefore, plays a critical role in alleviating propionyl CoA toxicity in mycobacteria by inactivating acyl CoA synthetase (ACS). The precision by which mycobacteria can regulate the metabolism of fatty acids in a cAMP-dependent manner appears to be unparalleled in other biological organisms and is ideally suited to adapt to the complex environment that pathogenic mycobacteria experience in the host.

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B-myb antisense oligonucleotides inhibit proliferation of human hematopoietic cell lines

Blood ◽

10.1182/blood.v79.10.2708.2708 ◽

1992 ◽

Vol 79 (10) ◽

pp. 2708-2716 ◽

Cited By ~ 65

Author(s):

M Arsura ◽

M Introna ◽

F Passerini ◽

A Mantovani ◽

J Golay

Keyword(s):

Cell Lines ◽

Antisense Oligonucleotides ◽

Hematopoietic Cell ◽

Dependent Manner ◽

Myb Gene ◽

Myb Genes ◽

Dose Dependent ◽

Lymphoid Cell Lines ◽

Hematopoietic Cell Lines

Abstract The B-myb gene is highly homologous to the c-myb protooncogene in several domains and also shares some of the functions of c-myb in that it can act as a transcriptional activator. In addition, the expression of both the B-myb and c-myb genes correlates with proliferation of normal hematopoietic cells. We investigated more directly the role of B- myb in proliferation of hematopoietic cell lines using B-myb-specific antisense oligonucleotides. We showed that several anti-B-myb oligonucleotides, complementary to distinct regions of the gene, inhibit significantly and in a dose-dependent manner the proliferation of all myeloid or lymphoid cell lines tested. This block in proliferation was not accompanied by detectable differentiation of U937 or HL60 cells to macrophages or granulocytes either spontaneously or after exposure to chemical agents. These data suggest that the B-myb gene, like c-myb, is necessary for hematopoietic cell proliferation.

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Poster 14: RGD Peptide Inhibits Adhesion of Pleomorphic Adenoma Cell Lines to Fibronectin in a Dose-Dependent Manner

Otolaryngology ◽

10.1016/s0194-5998(96)80638-3 ◽

1996 ◽

Vol 115 (2) ◽

pp. P81-P82

Author(s):

Melissa G. Steiner ◽

Elaina F. George ◽

John F. Carew ◽

William I. Kuhel ◽

W. Shain Schley

Keyword(s):

Pleomorphic Adenoma ◽

Cell Lines ◽

Rgd Peptide ◽

Dependent Manner ◽

Adenoma Cell ◽

Dose Dependent

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A Fully Human Antagonist Anti-CD40 Antibody Triggers Significant Antitumor Activity Against Human Multiple Myeloma.

Blood ◽

10.1182/blood.v104.11.2414.2414 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2414-2414

Author(s):

Yu-Tzu Tai ◽

Xian-Feng Li ◽

Xia Tong2 ◽

Laurence Catley ◽

Daniel Santos ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Lines ◽

Mononuclear Cells ◽

Human Peripheral Blood ◽

Dependent Manner ◽

Peripheral Blood Mononuclear ◽

Specific Lysis ◽

Growth And Survival ◽

Human Multiple Myeloma ◽

Dose Dependent

Abstract We previously demonstrated that CHIR-12.12, a fully human anti-CD40 mAb (IgG1) generated in XenoMouseÒ mice (Abgenix, Inc), blocks CD40/CD40 ligand (CD40L) interactions and has more potent anti-lymphoma activity than Rituximab both in vivo and in vitro (abstract #2386, ASH, San Diego, Dec. 2003). In this study, we assess the efficacy of CHIR-12.12 against human multiple myeloma (MM) using CD40-expressing MM cell lines and purified CD138+ patient cells. CHIR-12.12 binds to purified CD138+ MM cells in >80% (10/12) of patient samples, as measured by flow cytometry: the mean fluorescence intensity (MFI) range was 1 to 20 for CHIR-12.12 vs 0.2–0.9 for control human IgG1. We next examined the antagonist activity of CHIR-12.12 in MM cells. CHIR-12.12 blocked CD40L-mediated proliferation of CD40-expressing MM lines and purified CD138+ patient cells from 2 MM patients in a dose-response manner. In contrast, CHIR-12.12 alone did not alter constitutive MM cell proliferation. Immunoblotting analysis demonstrated that PI3-K/AKT, NF-kB, and ERK activation induced by hCD40L in the 12BM MM cell line was significantly inhibited by CHIR-12.12 (5 μg/ml). Adhesion of MM cells to bone marrow stromal cells (BMSCs) confers growth and survival benefit for tumor cells. Since CD40 activation, either by stimulatory mouse anti-CD40 mAb G28.5 or formaldehyde-fixed CHO cells expressing hCD40L, induces MM cell adhesion to fibronectin (FN) or BMSCs, we next asked whether antagonist CHI12.12 abrogates this process. CHIR-12.12 inhibited CD40L-induced adhesion of MM cell lines to FN in a dose dependent manner (0.001-10 μg/ml), whereas control human IgG did not. Moreover, CHIR-12.12 (1 μg/ml) blocked hCD40L-induced adhesion of freshly isolated patient MM cells to BMSCs. Adhesion of MM cells to BMSCs induces IL-6 secretion, an important growth and survival cytokine for MM cells, and treatment of MM cells with hCD40L further augmented adhesion-induced IL-6 secretion. Conversely, pretreatment of CD40-expressing MM cell lines with CHIR-12.12 significantly decreased IL-6 secretion triggered by coculture of MM cells with BMSCs. We next examined whether CHIR-12.12 stimulates antibody-dependent cellular cytotoxicity (ADCC) against CD40-expressing MM cells. Human peripheral blood mononuclear cells and purified NK cells (CD56+CD3−) were used as effector cells. CHIR-12.12 triggered MM cell lysis in a dose dependent manner, as measured in CD40-expressing MM cell lines. The maximum specific lysis of 20–70 % was achieved at 10 μg/ml concentration of CHIR-12.12. CHIR-12.12 mediated lysis was specific to CD40-expressing MM cells, as CHIR-12.12 did not induce ADCC against CD40-negative MM cells. Importantly, CHIR-12.12 induced ADCC against CD138+ cells isolated from 2 MM patients. These results provide preclinical rationale for clinical evaluation of CHIR-12.12 with the goal of improving patient outcome in MM.

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Lenalidomide Strongly Enhances Natural Killer (NK) Cell Mediated Antibody-Dependent Cellular Cytotoxicity (ADCC) of Rituximab Treated Non-Hodkin’s Lymphoma Cell Lines In Vitro.

Blood ◽

10.1182/blood.v108.11.3714.3714 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3714-3714 ◽

Cited By ~ 2

Author(s):

Lei Wu ◽

Peter Schafer ◽

George Muller ◽

David Stirling ◽

J. Blake Bartlett

Keyword(s):

Nk Cells ◽

Tumor Cells ◽

Cell Lines ◽

Nk Cell ◽

Dependent Manner ◽

Activation Markers ◽

Early Results ◽

Ifn Γ ◽

Dose Dependent

Abstract Lenalidomide (Revlimid® is approved for the treatment of transfusion-dependent patients with anemia due to low- or intermediate-1-risk MDS associated with a del 5q cytogenetic abnormality with or without additional cytogenetic abnormalities, and in combination with dexamethasone is for the treatment of multiple myeloma patients who have received at least one prior therapy. Encouraging early results suggest a potential for clinical efficacy in B cell non-Hodgkin’s lymphoma (NHL). Potential mechanisms of action include anti-angiogenic, anti-proliferative and immunomodulatory activities. Lenalidomide has been shown to enhance Th1-type cytokines and T cell and NK cell activation markers in patients with advanced cancers. Furthermore, lenalidomide has been shown to enhance rituximab-mediated protection in a SCID mouse lymphoma model in vivo. We have utilized an in vitro ADCC system to assess the ability of lenalidomide to directly enhance human NK cell function in response to therapeutic antibodies, such as rituximab (chimeric anti-CD20 mAb). Isolated NK cells produced little or no IFN-γ in response to IgG and/or IL-2 or IL-12. However, pre-treatment of NK cells with lenalidomide greatly enhanced IFN-γ production by NK cells in a dose-dependent manner. In a functional ADCC assay, NHL cell lines (Namalwa, Farage & Raji) were pre-coated with rituximab and exposed to NK cells pre-treated with lenalidomide in the presence of either exogenous IL-2 or IL-12. After 4 hours in culture the viability of the tumor cells was assessed. Lenalidomide consistently and synergistically increased the killing of tumor cells in a dose-dependent manner and up to >4-fold compared to rituximab alone. Rituximab alone had only a small effect in this model and there was no killing of cells in the absence of rituximab. The presence of either exogenous IL-2 or IL-12 was required to see enhanced killing by lenalidomide. In cancer patients lenalidomide has been shown to increase serum IL-12 levels and is also known to induce IL-2 production by T cells in vitro. Potential mechanisms for enhanced ADCC include increased signaling through NK FCγ receptors and/or IL-2 or IL-12 receptors. However, we found that these receptors are unaffected by lenalidomide, although downstream effects on NK signaling pathways are likely and are being actively investigated. In conclusion, we have shown that lenalidomide strongly enhances the ability of rituximab to induce ADCC mediated killing of NHL cells in vitro. This provides a strong rationale for combination of these drugs in patients with NHL and CLL.

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Clarithromicin Induces Autophagy in Myeloma Cells.

Blood ◽

10.1182/blood.v108.11.3509.3509 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3509-3509 ◽

Cited By ~ 2

Author(s):

Miki Nakamura ◽

Takahiro Kamimoto ◽

Tamotsu Yoshimori ◽

Hiroaki Mitsuya ◽

Hiroyuki Hata

Keyword(s):

Electron Microscopy ◽

Growth Inhibition ◽

Cell Lines ◽

Fluorescent Microscopy ◽

Myeloma Cell ◽

Pi3 Kinase ◽

Dependent Manner ◽

Myeloma Cells ◽

Akt Phosphorylation ◽

Dose Dependent

Abstract Introduction Some macrolide antibiotics exert effects other than anti-bacterial activity on the growth and viability of certain cancer cells. The presence of cytoplasmic vacuoles is one the salient features of autophagy, a cellular event believed to recycle cellular ingredients under nutrient-starved conditions. Such vacuoles (autophagosomes) fuse with lysozomes, generating autolysozomes toward later stages of autophagy, digesting organelles and degenerated proteins. Our own and others’ findings that a macrolide antibiotic clarithromicin (CAM) occasionally shows anti-myeloma effects when combined with thalidomide and/or dexamethasone prompted us to examine CAM for its effects on myeloma cells in vitro. Methods Four myeloma cell lines (12PE, KHM-11, KMM-1 and U266) and primary myeloma cells purified by CD138-conjugated immune-magnetic beads (Miltenvi Biotec, Auburn, CA) were utilized. Clarithromicin was obtained from Taisho-Toyama pharmaceuticals (Tokyo, JAPAN). Morphology was analyzed either by May-Giemza staining or electron microscopy. Autolysozome was stained with Lysotracker (Invitrogen, Carlsbad, CA) and analyzed using fluorescent microscopy. Antibody to LC3 was obtained from Dr. T. Yoshimori (Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University). Results and discussion CAM induced vacuoles in the cytoplasm of both myeloma cell lines and primary myeloma cells at concentrations ranging from 10 to 50 mg/ml at a dose-dependent manner after ~18 hours treatment. Electron microscopy revealed that those vacuoles morphologically resemble autolysozomes. To further confirm the identity of autolysozomes, cells were stained with Lysotracker, which specifically stains acid lysozome. After the treatment with CAM, the accumulation of vacuoles in the cytoplasm, stained with Lysotacker, was observed. Since initiation of autophagy depends on PI3-kinase, we investigated whether CAM induced AKT phosphorylation. AKT phosphorylation was readily observed, and moreover, the emergence of vacuoles stainable with Lysotracker was inhibited when the cells were pretreated with PI3-kinase inhibitors, 3MA or LY294002, strongly suggesting that vacuolation is indeed mediated with PI3-kinase. To further confirm that autopahgy is induced by CAM, the process of LC3-I to LC3-II, a hallmark of autophagy, was examined. We found that the induction of LC3-II by CAM occurred at a dose-dependent manner. Taken together, these findings strongly suggest that CAM induces autolysozome accumulation through activating PI3-kinase. Finally, we examined whether CAM induced apoptosis when combined with thalidomide. Three myeloma cells lines, which abundantly expressed Bcl-2, showed no growth inhibition, while KHM-11, which was defective in Bcl-2, showed marked apoptosis and growth inhibition with the combination of CAM and thalidomide, suggesting that CAM might potentially augment anti-myeloma activity of thalidomide although the mechanisms are to be determined. Taken these observations together, the manipulation of certain autophagy processes with reagents such as macrolides (i.e., CAM) might represent a new therapeutic approach in the treatment of myeloma. We hypothesize that CAM dually functions in the event of autophagy, i.e., it initiates autophagy while it suppresses autophagy at later stages. Further study under the hypothesis is currently underway.

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