Low dose cepharanthine ameliorates immune thrombocytopenic purpura associated with multiple myeloma

doi:10.1016/j.intimp.2012.04.015

International Immunopharmacology

Volume 13, Issue 3, July 2012, Pages 242-244

https://doi.org/10.1016/j.intimp.2012.04.015 Get rights and content

Abstract

Immune thrombocytopenic purpura associated with multiple myeloma is extremely rare. Here, we present the successful management of an elderly Japanese patient with multiple myeloma complicated by immune thrombocytopenia with low dose cepharanthine — a plant derived alkaloid. A 78-year-old male patient with IgGκ multiple myeloma was repetitively treated with melpharan and prednisolone. In each chemotherapy course, we demonstrated a close relationship between platelet recovery and administration of high dose prednisolone. When further chemotherapy was avoided because of the patient's poor general condition, administration of cepharanthine was effective in halting progressive thrombocytopenia due to abnormal immune mechanisms. We propose the usefulness of cepharanthine in management of this rare disease.

Introduction

Immune thrombocytopenic purpura (ITP) is sometimes associated with B cell lymphoproliferative diseases. However, its association with multiple myeloma (MM) is extremely rare. To date, only seven cases of ITP with MM have been reported in the literature. Here, we present the successful management of thrombocytopenia in an elderly Japanese patient with MM complicated by ITP with low dose cepharanthine.

Section snippets

Case presentation

A 78-year-old man was admitted to the hospital with severe lumbar pain. He had no previous history of hematological or autoimmune diseases. Laboratory findings revealed WBC 3.08 × 10⁹/l (Neutrophils 41.6%, Lymphocytes 53.6%, Monocytes 4.2%, Eosinophils 0.6%), RBC 3.58 × 10¹²/l, Hb 11.3 g/dl, and platelet count 139 × 10⁹/l. Prothrombin time, activated partial thromboplastin time, and fibrinogen were normal (87%, 32 s, and 232 mg/dl, respectively). Serum total protein and IgG levels were elevated (9.5 g/dl

Discussion

In patients with MM, thrombocytopenia is occasionally observed due to replacement of bone marrow by myeloma cells or bone marrow suppression induced by chemotherapy. In the present case, however, re-examined bone marrow aspiration, when peripheral platelet severely decreased (44 months after diagnosis), demonstrated that megakaryocytes were reserved in spite of extreme decreases in other normal bone marrow cells due to expansion of myeloma cells. Also, at that time, PAIgG was elevated. PAIgG has

Funding

We have no funding support.

Conflict of interest

We declare that we have no conflict of interest.

Author contribution

Tabata R, Tazoh A, and Nagai T treated the patient and approved the article, Tabata R and Tabata C interpreted the data and drafted the article.

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Successful management of immune thrombocytopenic purpura with thalidomide in a patient with multiple myeloma
Hematol J
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There are more references available in the full text version of this article.

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Cepharanthine inhibits influenza A virus replication by impairing viral polymerase activity and regulating influenza-induced immune response
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Cepharanthine (CEP), a natural bis-benzylisoquinoline alkaloid extracted from the plant Stephania cephalantha Hayata, has been widely used to treat several acute and chronic diseases. However, its antiviral potential against influenza A virus (IAV) infection remains unknown.
The study aims to assess the antiviral and immunomodulatory effects of CEP in vivo and in vitro and investigate its underlying antiviral mechanisms.
Antiviral and anti-inflammatory activities of CEP were assessed in MDCK, A549 and RAW264.7 cells infected with influenza virus. Proinflammatory cytokine levels were measured by qRT-PCR and ELISA. The anti-influenza effect and underlying antiviral mechanism of CEP were mainly determined by MTT assay, plaque reduction assay, time-of-addition and mini-replicon assay. The inhibition of CEP on IAV-induced activation of innate immune signaling was detected by western blotting. Furthermore, BALB/c mice were infected intranasally with A/PR/8/34 (H1N1) virus and treated with CEP (60, 30, 15 mg/kg/d) or oseltamivir (60 mg/kg/d). The changes in body weight, survival rates, viral titers, proinflammatory cytokine levels and pathological parameters were detected.
CEP exhibited antiviral effects against multiple IAV strains, while also demonstrating anti-inflammatory effects in influenza virus-infected RAW264.7 and A549 cells. The results of the mechanism study indicated that CEP effectively suppressed IAV replication by limiting viral polymerase activity. On the other hand, CEP could modulate pro-inflammatory responses via inhibition of janus kinase/signal transducer and activator of transcription/ nuclear factor kappa B (JAK/STAT/NF‑κB) signaling pathways involved in influenza virus pathogenesis. Treatment of mice with CEP improved the survival rate and body weight of influenza virus-infected mice, reduced viral titers and alleviated influenza virus-induced pathological damage and inflammation in mouse lung tissue.
Collectively, the anti-influenza virus property of CEP was a result of inhibiting viral polymerase activity and preventing virus-induced excessive inflammation, highlighting it might be an oral medication for the treatment of IAV infection.
Genetics and epigenetics of autoimmune thyroid diseases: Translational implications
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Citation Excerpt :
In the aforementioned humanized mouse models, Cepharanthine demonstrated an inhibitory effect on T-cell stimulation and its downstream cytokine production. Cepharanthine is an alkaloid extracted from the plant Stephania cepharantha Hayata that, curiously, has been used for more than 40 years in Japan for several chronic and acute conditions [51], including immune thrombocytopenic purpura associated with multiple myeloma [52], radiation-induced leukopenia [53,54], and even venomous snakebites [55]. Cepharanthine has also been reported to have other beneficial effects such as anti-tumor [56] and anti-allergic activities [57] and multidrug resistance reversal [58].
Hashimoto's thyroiditis (HT) and Graves' disease (GD) are prevalent autoimmune disorders, representing opposite ends of the clinical spectrum of autoimmune thyroid diseases (AITD). The pathogenesis involves a complex interplay between environment and genes. Specific susceptibility genes have been discovered that predispose to AITD, including thyroid-specific and immune-regulatory genes. Growing evidence has revealed that genetic and epigenetic variants can alter autoantigen presentation during the development of immune tolerance, can enhance self-peptide binding to MHC (major histocompatibility complex), and can amplify stimulation of T- and B-cells. These gene-driven mechanistic discoveries lay the groundwork for novel treatment targets. This review summarizes recent advances in our understanding of key AITD susceptibility genes (Tg¹, TSHR, HLA-DR3, and CD40) and their translational therapeutic potential.
Antinociceptive activities and mechanism of action of Cepharanthine
2022, Biochemical and Biophysical Research Communications
Citation Excerpt :
It is the only medicine in the wide class of bisbenzylisoquinoline alkaloids that has been approved for human use, and it exhibits anti-inflammatory [11], anti-oxidation [12], anti-viral [13], immunological modulation [14], anti-cancer [15] and anti-parasitic properties [12]. Cepharanthine holds promise for treating a wide range of diseases, such as radiation-induced leukopenia [16], idiopathic thrombocytopenic purpura [17], refractory anemia, alopecia areata and sarcoidosis [18]. It is reported that Cepharanthine is well tolerated and safe with very limited undesirable effects [12].
Cepharanthine is an alkaloid that isolated from Stephania cepharantha Hayata, however，its analgesic properties are unclear and the molecular targets that mediating Cepharanthine-induced analgesia are not explored yet. In the current study, mice pain models including hot plate, acetic acid-induced writhing and formalin tests were conducted to evaluate the antinociceptive actions of Cepharanthine. [³H]-ligand competitive binding assay was applied to determine the binding affinity and selectivity of Cepharanthine at κ, μ and δ opioid receptors. Cepharanthine-induced constipation was investigated using the small intestinal transit test. The results showed that intraperitoneal injection of Cepharanthine produced potent antinociception with an ED₅₀ value of 24.5 mg/kg in the acetic acid-induced writhing test. In the formalin test, Cepharanthine produced moderate antinociception with the maximum analgesic activity of 42.6 ± 11.3% in phase I and 60.1 ± 7.7% in phase Ⅱ, respectively. Cepharanthine had no effects in the hot plate test. In vitro radioligand binding assay, Cepharanthine exhibited a high affinity for μ opioid receptors with a Ki value of 80 nM, without binding to κ and δ opioid receptors. Correspondingly, Cepharanthine-mediated antinociceptive effects were antagonized by pretreatment with opioid receptor antagonist naloxone. Cepharanthine also decreased the small intestine propulsion rates in the small intestinal transit test. Together, this study firstly demonstrates that Cepharanthine produces potent antinociception in acetic acid-induced visceral pain and moderate antinociception in formalin-induced inflammatory pain, and its mechanism of action may be through activation of μ opioid receptors.
Molecular mechanisms and therapeutic implications of tetrandrine and cepharanthine in T cell acute lymphoblastic leukemia and autoimmune diseases
2021, Pharmacology and Therapeutics
Citation Excerpt :
Our previous studies suggested that these two bisbenzylisoquinoline alkaloids, tetrandrine and cepharanthine, show special inhibitory efficacies on abnormally activated T cells or steroid resistant human leukemia T cells (Liu, Hirano, Tanaka, Onda, & Oka, 2003; Xu et al., 2017; Xu et al., 2017; Xu et al., 2019). Similar evidence from other numerous studies also supported the medical application of these two natural compounds with immunoregulatory and anti-cancer potencies (Bailly, 2019; Bhagya & Chandrashekar, 2018; Bhagya & Chandrashekar, 2016; Lai, 2002; Liu, Liu, & Li, 2016; Rogosnitzky & Danks, 2011; Tabata, Tabata, Tazoh, & Nagai, 2012). Furthermore, previous clinical trial suggested that tetrandrine was potentially useful for the treatment of refractory and relapsed acute myelogenous leukemia (Xu et al., 2006).
Inappropriately activated T cells mediate autoimmune diseases and T cell acute lymphoblastic leukemia (T-ALL). Glucocorticoid and chemotherapeutic agents have largely extended lives of these patients. However, serious side effects and drug resistance often limit the prognosis of considerable number of the patients. The efficient treatment of autoimmune diseases or T-ALL with drug resistance remains an important unmet demand clinically. Bisbenzylisoquinoline alkaloids tetrandrine and cepharanthine have been applied for the treatment of certain types of autoimmune diseases and cancers, while studies on their action mechanisms and their further applications combined with glucocorticoids or chemotherapeutic agents remains to be expanded. This review introduced molecular mechanisms of tetrandrine and cepharanthine in T cells, including their therapeutic implications. Both tetrandrine and cepharnthine influence the growth of activated T cells via several kinds of signaling pathways, such as NF-κB, caspase cascades, cell cycle, MAPK, and PI3K/Akt/mTOR. According to recent preclinical and clinical studies, P-glycoprotein inhibitory effect of tetrandrine and cepharnthine could play a significant role on T cell-involved refractory diseases. Therefore, tetrandrine or cepharanthine combined with glucocorticoid or other anti-leukemia drugs would bring a new hope for patients with glucocorticoid-resistant autoimmune disease or refractory T-ALL accompanied with functional P-glycoprotein. In conclusion, bisbenzylisoquinoline alkaloids tetrandrine and cepharanthine can regulate several signaling pathways in abnormally activated T cells with low toxicity. Bisbenzylisoquinoline alkaloids deserve to be paid more attention as a lead compound to develop new drugs for the treatment of T cell-involved diseases in the future.
Cepharanthine blocks TSH receptor peptide presentation by HLA-DR3: Therapeutic implications to Graves’ disease
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We have previously identified a signature HLA-DR3 pocket variant, designated HLA-DRβ1-Arg74 that confers a high risk for Graves' Disease (GD). In view of the key role of HLA-DRβ1-Arg74 in triggering GD we hypothesized that thyroid-stimulating hormone receptor (TSHR) peptides that bind to the HLA-DRβ1-Arg74 pocket with high affinity represent key pathogenic TSHR peptides triggering GD, and that blocking their presentation to CD4⁺ T-cells can be used as a novel therapeutic approach in GD. There were several previous attempts to identify the major pathogenic TSHR peptide utilizing different methodologies, however the results were inconsistent and inconclusive. Therefore, the aim of our study was to use TSHR peptide binding affinity to HLA-DRβ1-Arg74 as a method to identify the key pathogenic TSHR peptides that trigger GD. Using virtual screening and ELISA and cellular binding assays we identified 2 TSHR peptides that bound with high affinity to HLA-DRβ1-Arg74 - TSHR.132 and TSHR.197. Peptide immunization studies in humanized DR3 mice showed that only TSHR.132, but not TSHR.197, induced autoreactive T-cell proliferation and cytokine responses. Next, we induced experimental autoimmune Graves’ disease (EAGD) in a novel BALB/c-DR3 humanized mouse model we created and confirmed TSHR.132 as a major DRβ1-Arg74 binding peptide triggering GD in our mouse model. Furthermore, we demonstrated that Cepharanthine, a compound we have previously identified as DRβ1-Arg74 blocker, could block the presentation and T-cell responses to TSHR.132 in the EAGD model.
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Citation Excerpt :
CEP therapy, alone or in combination with prednisolone, improves symptoms of chronic immune thrombocytopenia (Takahata et al., 2012). The drug was found to be effective in halting the progression of immune thrombocytopenic purpura in a patient with multiple myeloma (Tabata et al., 2012). A link can be established between the capacity of CEP to inhibit the platelet activation and its capacity to alter phospholipid dynamics and functions.
Cepharanthine (CEP) is a drug used in Japan since the 1950s to treat a number of acute and chronic diseases, including treatment of leukopenia, snake bites, xerostomia and alopecia. It is the only approved drug for Human use in the large class of bisbenzylisoquinoline alkaloids. This natural product, mainly isolated from the plant Stephania cephalantha Hayata, exhibits multiple pharmacological properties including anti-oxidative, anti-inflammatory, immuno-regulatory, anti-cancer, anti-viral and anti-parasitic properties.
The mechanism of action of CEP is multifactorial. The drug exerts membrane effects (modulation of efflux pumps, membrane rigidification) as well as different intracellular and nuclear effects. CEP interferes with several metabolic axes, primarily with the AMP-activated protein kinase (AMPK) and NFκB signaling pathways. In particular, the anti-inflammatory effects of CEP rely on AMPK activation and NFκB inhibition.
In this review, the historical discovery and development of CEP are retraced, and the key mediators involved in its mode of action are presented. The past, present, and future of CEP are recapitulated. This review also suggests new opportunities to extend the clinical applications of this well-tolerated old Japanese drug.

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International Immunopharmacology

Abstract

Introduction

Section snippets

Case presentation

Discussion

Funding

Conflict of interest

Author contribution

References (13)

The pathogenesis of chronic immune thrombocytopenic purpura

Semin Hematol

Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP

Blood

Therapeutic potential of the biscoclaurine alkaloid, cepharanthine, for a range of clinical conditions

Pharmacol Rep

Multiple myeloma associated with immune thrombocytopenic purpura

Cancer

Multiple myeloma and immune thrombocytopenia

Clin Lab Haematol

Successful management of immune thrombocytopenic purpura with thalidomide in a patient with multiple myeloma

Hematol J

Cited by (20)

Cepharanthine inhibits influenza A virus replication by impairing viral polymerase activity and regulating influenza-induced immune response

Genetics and epigenetics of autoimmune thyroid diseases: Translational implications

Antinociceptive activities and mechanism of action of Cepharanthine

Molecular mechanisms and therapeutic implications of tetrandrine and cepharanthine in T cell acute lymphoblastic leukemia and autoimmune diseases

Cepharanthine blocks TSH receptor peptide presentation by HLA-DR3: Therapeutic implications to Graves’ disease

Cepharanthine: An update of its mode of action, pharmacological properties and medical applications

Preliminary reportLow dose cepharanthine ameliorates immune thrombocytopenic purpura associated with multiple myeloma

Abstract

Introduction

Section snippets

Case presentation

Discussion

Funding

Conflict of interest

Author contribution

Semin Hematol

Blood

Pharmacol Rep

Multiple myeloma associated with immune thrombocytopenic purpura

Cancer

Multiple myeloma and immune thrombocytopenia

Clin Lab Haematol

Successful management of immune thrombocytopenic purpura with thalidomide in a patient with multiple myeloma

Hematol J

Preliminary report
Low dose cepharanthine ameliorates immune thrombocytopenic purpura associated with multiple myeloma