Combination treatment with 2-methoxyestradiol overcomes bortezomib resistance of multiple myeloma cells

송인성,이성률,정유정,정승훈,허혜진,김형규,고태희,고경수,김나리,이병두,염재범,한진 생화학분자생물학회 2013 Experimental and molecular medicine Vol.45 No.10

Bortezomib is a proteasome inhibitor used for the treatment of relapsed/refractory multiple myeloma (MM). However, intrinsic and acquired resistance to bortezomib has already been observed in MM patients. In a previous report, we demonstrated that changes in the expression of mitochondrial genes lead to changes in mitochondrial activity and bortezomib susceptibility or resistance, and their combined effects contribute to the differential sensitivity or resistance of MM cells to bortezomib. Here we report that the combination treatment of bortezomib and 2-methoxyestradiol (2ME), a natural estrogen metabolite, induces mitochondria-mediated apoptotic cell death of bortezomib-resistant MM KMS20 cells via mitochondrial reactive oxygen species (ROS) overproduction. Bortezomib plus 2ME treatment induces a higher level of cell death compared with treatment with bortezomib alone and increases mitochondrial ROS and Ca2þ levels in KMS20 cells. Pretreatment with the antioxidant N-acetyl-L-cysteine scavenges mitochondrial ROS and decreases cell death after treatment with bortezomib plus 2ME in KMS20cells. Moreover, we observed that treatment with bortezomib plus 2ME maintains the activation of c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase kinase kinase 4/7 (MKK4/7). Collectively, combination treatment with bortezomib and 2ME induces cell death via JNK-MKK4/7 activation by overproduction of mitochondrial ROS. Therefore, combination therapy with specific mitochondrial-targeting drugs may prove useful to the development of novel strategies for the treatment of bortezomib-resistant MM patients.

Establishment and characterization of bortezomib-resistant U266 cell line: Constitutive activation of NF-κB-mediated cell signals and/or alterations of ubiquitylation-related genes reduce bortezomib-induced apoptosis?

( Ju Won Park ),( Eun Kyung Bae ),( Chan Su Lee ),( Jee Hye Choi ),( Woo June Jung ),( Kwang Sung Ahn ),( Sung Soo Yoon ) 생화학분자생물학회 2014 BMB Reports Vol.47 No.5

Bortezomib has been known as the most promising anti-cancerdrug for multiple myeloma (MM). However, recent studiesreported that not all MM patients respond to bortezomib. Toovercome such a stumbling-block, studies are needed to clarifythe mechanisms of bortezomib resistance. In this study, weestablished a bortezomib-resistant cell line (U266/velR), andexplored its biological characteristics. The U266/velR showedreduced sensitivity to bortezomib, and also showed crossresistanceto the chemically unrelated drug thalidomide. U266/velR cells had a higher proportion of CD138 negative subpopulation,known as stem-like feature, compared to parentalU266 cells. U266/velR showed relatively less inhibitory effectof prosurvival NF-κB signaling by bortezomib. Further analysisof RNA microarray identified genes related to ubiquitinationthat were differentially regulated in U266/velR. Moreover, theexpression level of CD52 in U266 cells was associated withbortezomib response. Our findings provide the basis for developingtherapeutic strategies in bortezomib-resistant relapsed andrefractory MM patients.[BMB Reports 2014; 47(5): 274-279]

Poor prognostic significance of Mycobacterium tuberculosis infection during bortezomib-containing chemotherapy in patients with multiple myeloma

안재숙,류성윤,양덕환,정성훈,강승지,김미영,이승신,김여경,김형준,이제중 대한혈액학회 2013 Blood Research Vol.48 No.1

Background Bortezomib administration leads to a transient decrease in CD4+ T cells, increasing the susceptibility to opportunistic infections. The activation and proliferation of CD4+ T cells are particularly important in the host’s defense against tuberculosis infection. The aim of this study was to determine the incidence and clinical significance of tuberculosis infection in patients with multiple myeloma (MM) treated with a bortezomib-containing regimen. Methods We retrospectively investigated the incidence of Mycobacterium tuberculosis in 115 patients with MM who were given a bortezomib-containing regimen and studied the disease prognosis. Results All patients received chemotherapy prior to bortezomib administration, and the median duration from diagnosis to bortezomib administration was 12.4 months (range, 0.2‒230). We diagnosed tuberculosis in 8 patients (8/115, 7%): 7 patients had a pulmonary granulomatous lesion prior to chemotherapy and 1 developed reactivation of tuberculosis, but none of them died of uncontrolled tuberculosis infection. In 50% of patients with tuberculosis, bortezomib-containing therapy was interrupted. This resulted in significantly lower response rates to the bortezomib-containing therapy (P<0.05) and significantly shorter overall survival times amongst tuberculosis vs. non-tuberculosis patients (P=0.017). Conclusion Tuberculosis infection was not uncommon among the patients with MM who were treated with bortezomib-containing therapy, and tuberculosis infection in these patients resulted in an interruption of bortezomib administration, which significantly affected patient outcomes. Therefore, early diagnosis and treatment of tuberculosis infection are critical to avoid worsening outcomes in such patients.

Bortezomib (Velcade(R)) 항암치료의 부작용으로 발생한 피부의 림프구성 혈관염

이경진 ( Kyung Jin Lee ),김정은 ( Jung Eun Kim ),박현정 ( Hyun Jeong Park ),이준영 ( Jun Young Lee ),조백기 ( Baik Kee Cho ) 대한피부과학회 2009 대한피부과학회지 Vol.47 No.12

Bortezomib (Velcade(R)) is a newly developed chemotherapeutic agent that is mainly used for the treatment of multiple myeloma. It is a selective and reversible inhibitor of proteasome, which is a multicatalytic enzyme complex found in the cytoplasm of all eukaryotic cells. Its therapeutic target is nuclear factor-kappa B (NF-κB), which is a kind of transcription factor. Bortezomib blocks inhibitory κB protein degradation, it prevents NF-κB activation and it induces apoptosis in multiple myeloma cells. Its side effects are known to be fatigue, gastrointestinal symptoms, thrombocytopenia and peripheral neuropathy. However, little is known about its cutaneous adverse effects. A 76 year-old patient with multiple myeloma had been treated with MP (melphalan and prednisone) chemotherapy, but the treatment was not effective. Therefore, the chemotherapeutic regimen was changed to bortezomib only. Two days after the first administration of bortezomib, multiple erythematous papules and purpuric patches on the trunk and both extremities developed. The cutaneous symptoms improved after the discontinuation of bortezomib. However, the skin lesion was aggravated during the 2nd bortezomib chemotherapeutic cycle and new erythematous papules developed on his face during the 3rd bortezomib chemotherapeutic cycle. The histopathologic finding showed predominant lymphocytic infiltration with some eosinophils around the vessel walls in combination with red blood cell extravasation. Herein, we report on a 76-year-old male patient with multiple myeloma and who developed cutaneous vasculitis after the administration of bortezomib. (Korean J Dermatol 2009;47(12):1392∼1396)

Poor prognostic significance of Mycobacterium tuberculosis infection during bortezomib-containing chemotherapy in patients with multiple myeloma

안재숙,류성윤,양덕환,정성훈,강승지,김미영,이승신,김여경,김형준,이제중 대한혈액학회 2013 Blood Research Vol.48 No.1

Background Bortezomib administration leads to a transient decrease in CD4+ T cells, increasing the susceptibility to opportunistic infections. The activation and proliferation of CD4+ T cells are particularly important in the host’s defense against tuberculosis infection. The aim of this study was to determine the incidence and clinical significance of tuberculosis infection in patients with multiple myeloma (MM) treated with a bortezomib-containing regimen. Methods We retrospectively investigated the incidence of Mycobacterium tuberculosis in 115 patients with MM who were given a bortezomib-containing regimen and studied the disease prognosis. Results All patients received chemotherapy prior to bortezomib administration, and the median duration from diagnosis to bortezomib administration was 12.4 months (range, 0.2‒230). We diagnosed tuberculosis in 8 patients (8/115, 7%): 7 patients had a pulmonary granulomatous lesion prior to chemotherapy and 1 developed reactivation of tuberculosis, but none of them died of uncontrolled tuberculosis infection. In 50% of patients with tuberculosis, bortezomib-containing therapy was interrupted. This resulted in significantly lower response rates to the bortezomib-containing therapy (P<0.05) and significantly shorter overall survival times amongst tuberculosis vs. non-tuberculosis patients (P=0.017). Conclusion Tuberculosis infection was not uncommon among the patients with MM who were treated with bortezomib-containing therapy, and tuberculosis infection in these patients resulted in an interruption of bortezomib administration, which significantly affected patient outcomes. Therefore, early diagnosis and treatment of tuberculosis infection are critical to avoid worsening outcomes in such patients.

Pathological adaptive responses of Schwann cells to endoplasmic reticulum stress in bortezomib‐induced peripheral neuropathy

Shin, Yoon Kyung,Jang, So Young,Lee, Hyun Kyoung,Jung, Junyang,Suh, Duk Joon,Seo, Su‐,Yeong,Park, Hwan Tae Wiley Subscription Services, Inc., A Wiley Company 2010 Glia Vol.58 No.16

<P><B>Abstract</B></P><P>Bortezomib, a proteasome inhibitor, has been considered as a promising anticancer drug in the treatment of recurrent multiple myeloma and some solid tumors. The bortezomib‐induced peripheral neuropathy (BIPN) is a prominent cause of dose‐limiting toxicities after bortezomib treatment. In this study, we found that BIPN in a mouse model is characterized by acute but transient endoplasmic reticulum (ER) damages to Schwann cells. These damaged Schwann cells exhibit abnormal outcomes from healing processes such as the myelination of Remak bundles. A morphometric analysis of polymyelinated Remak bundles revealed that the pathological myelination was not related to the axonal parameters that regulate the normal myelination process during development. In addition, demyelinating macrophages were focally infiltrated within endoneurium of the sciatic nerve. To identify the mechanism underlying these pathologies, we applied a gene microarray analysis to bortezomib‐treated primary Schwann cells and verified the changes of several gene expression in bortezomib‐treated sciatic nerves. The analysis showed that bortezomib‐induced ER stress was accompanied by the activation of several protective molecular chaperones and the down‐regulation of myelin gene expression. ER stress inducers such as thapsigargin and bredelfin A also suppressed the mRNA expression of myelin gene P0 at transcriptional levels. In addition, the expression of chemokines such as the macrophage chemoattractants Ccl3 and Cxcl2 was significantly increased in Schwann cells in response to bortezomib and ER stress inducers. Taken together, these observations suggest that the pathological adaptive responses of Schwann cells to bortezomib‐induced ER stress may, in part, participate in the development of BIPN. © 2010 Wiley‐Liss, Inc.</P>

Natural polyphenols antagonize the antimyeloma activity of proteasome inhibitor bortezomib by direct chemical interaction

Kim, Tae Young,Park, Jongmin,Oh, Bora,Min, Hyun Jung,Jeong, Tae-Sook,Lee, Jae Hoon,Suh, Cheolwon,Cheong, June-Won,Kim, Hyo Jung,Yoon, Sung-Soo,Park, Seung Bum,Lee, Dong Soon Blackwell Publishing Ltd 2009 British journal of haematology Vol.146 No.3

<P>Summary</P><P>Bortezomib is a therapeutic proteasome inhibitor with antimyeloma activity and polyphenols are well known compounds that exert antiproliferative effects against tumuors. We attempted to co-treat myeloma cells with bortezomib and polyphenols, anticipating a synergistic effect. However, the anticancer activity of bortezomib was blocked by the polyphenols. The structural features of the polyphenols correlated strikingly with their antagonistic effect; in particular, the presence or absence of a vicinal diol moiety was the key element for effective blockage of the anticancer function of bortezomib. We speculated that the vicinal diols in the polyphenols interact with the boronic acid of bortezomib and convert the active triangular boronic acid of bortezomib to an inactive tetrahedral boronate, thus abolishing the antimyeloma activity of bortezomib. We confirmed this hypothesis by <SUP>11</SUP>B nuclear magnetic resonance spectroscopy and an <I>in vitro</I> assay on multiple myeloma (MM) cell lines and primary myeloma cells from patients. Based on these findings, restriction of the intake of natural polyphenols in foods or vitamin supplements during bortezomib treatment in MM patients should be considered.</P>

다발성 골수종 환자에서 Bortezomib에 의한 말초신경병증 발생과 위험인자 분석

전아영,김성환,김귀숙,이혜숙,김향숙 한국병원약사회 2014 병원약사회지 Vol.31 No.3

Bortezomib acts by disrupting ubiquitin-proteasome pathway which regulates proteinhomeostasis within the cell and has demonstrated significant activity mainly against recurrent ornewly diagnosed multiple myeloma(MM). Among bortezomib-related side effects, peripheral neuropathy(PN) as main dose-limiting non-haematological toxicity can substantially affect thequality of life of patients. It typically requires dose-reduction, delay, or even premature terminationof successful treatment. Therefore, predicting the risk for neuropathy before the therapyand a proper management of neurotoxicity are very important considerations. The aim of this study was to evaluate the incidence of PN, risk factors, and prior exposure topotentially neurotoxic chemotherapy. A total of 108 patients with multiple myeloma(MM) wereincluded, who received bortezomib in Seoul National University of Hospital(SNUH) from May 2005 to April 2008. A retrospective chart review was performed on SNUH patients’ElectronicMedical Records(EMR), and the SPSS Statistics 19.0 was used for analysis. In univariate analysis, no correlation was found between the development of PN, sex, or age,but creatinine level (Scr≥2)(48% vs 78%, p=0.007, OR=0.264), presence of DM(50% vs 76%,p=0.034, OR=0.324) and number of therapy cycles(N>3)(84% vs 57%, p=0.002, OR=4.046) weresignificantly correlated with PN incidence. In a multivariate logistic regression, the risk of bortezomib-related PN was lower in patients whose creatinine level was high(Scr≥2)(OR=0.248) andgreater in patients treated with high number of bortezomib cylces(N>3)(OR=4.235). Concerning that the prior exposure to chemotherapy could exacerbate neurotoxicity, there waslower incidence of PN in the prior bortezomib treated group(38% vs 62%, p=0.007), prior bortezomibwith thalidomide treated group(36% vs 63%, p=0.003), and prior bortezomib with vincristinetreated group(37% vs 60%, p=0.026).

신장이식 직후 발생한 불응성의 항체매개 거부반응에 대한 Bortezomib의 치료효과

김소정,전강웅,황정기,정병하,양철우,문인성,김지일,김미형 대한이식학회 2018 Korean Journal of Transplantation Vol.32 No.3

Bortezomib has been used to treat antibody-mediated rejection (AMR) that usually develops after kidney transplantation (KT). Although it has been used in various clinical situations, it is difficult to precisely define how the drug affects the clinical course. We used bortezomib to treat eight cases of AMR that developed immediately following KT in patients who were resistant to conventional treatment. Methods: Eight cases of refractory AMR that developed immediately after KT were treated with bortezomib on days 1, 4, 8, and 11. Results: The resolution rate was 75%, and the 2-year rejection-free survival rate was 83%. Six cases underwent immunologically high-risk KT. Six recovering patients exhibited clinical improvement within 2 weeks of the first dose of bortezomib and recovered completely within 2 months. The effects of bortezomib seemed to be prolonged; only one additional rejection episode was observed. The two failed patients never exhibited any clinical improvement and progressed aggressively to graft failure soon after transplantation. Their donor specific anti-human leukocyte antigen antibody were sustained at high levels. Conclusions: Bortezomib is an effective rescue therapy in patients with AMR that developed immediately after KT.

Bortezomib과 Dexamthasone으로 치료한 골수외 형질세포종 4예

백종현,이은영,장리라,손창배,신은경,서정아,이지숙,이호섭,이상민,신성훈,김양수 고신대학교의과대학 2007 고신대학교 의과대학 학술지 Vol.22 No.2

Despite the use of aggressive local and systemic treatment including autologous stem cell transplantation in multiple myeloma, extramedullary recurrences are common and the prognosis of these patients is poor. Many novel drugs such as thalidomide, lenalidomide and bortezomib improve the response of treatment of multiple myeloma, but some reports failed to describe thalidomide has effect in extramedullary plasmacytoma. Recent data report on the successful treatment plasmacytomas with bortezomib in patients with advanced multiple myeloma. We treated 4 relapsed or refractory extramedullary plasmacytomas with bortezomib at our institution. We recognized all these extramedullary plasmacytomas decreased and showed more than partial response. This report lends support to the efficacy of bortezomib in the treatment of plasmacytoma and describes the safe use of bortezomib. Responses may, however, be of short duration. Therefore, despite our limited experience, we propose that bortezomib may be considered a therapeutic option for such patients who have risk of radiation therapy