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Suppression of essential pro-inflammatory signaling pathways by natural agents for the therapy of Multiple Myeloma

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Abstract

Multiple myeloma (MM) is a malignant plasma cell tumor often arising in the bone marrow and is the most common non-Hodgkin’s haematological malignancy contributing 13 % of all malignancy and 1 % of neoplasia. MM arises from a pre-malignant condition known as ‘monoclonal gammapathy of undermined significance’. The aberrant antibodies that are produced leads to dysregulated humoral immunity. Studies in the last few years have revealed that various pro-inflammatory signaling pathways including nuclear factor-kappaB (NF-κB), signal transducer and activator of transcription 3 (STAT3), activator protein 1 (AP-1), phosphatidylinositol-3-kinase (PI3K/AKT), receptor Met and its ligand hepatocyte growth factor, and Wnt-β catenin play a pivotal role in the initiation and progression of MM. These signaling pathways can be induced by different pro-inflammatory cytokines and chemokines in MM cells. Hence, it is imperative to clearly dissect the role of various pro-inflammatory signaling pathways for the better understanding of the disease process and also for developing effective therapeutic interventions. In this review, we comprehensively analyze the detailed role of various pro-inflammatory signaling pathways involved in myeloma-genesis and its progression. Also, we discuss in detail the potential contribution of distinct inhibitors of pro-inflammatory signaling pathways derived from the natural sources that can be utilized both for the prevention and the treatment of MM.

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Abbreviations

AP-1:

Activator protein-1

APRIL:

A proliferation inducing ligand

ASK1:

Apoptosis signal-regulating kinase 1

BAD:

Bcl-2-associated death promoter

BAFF:

B-cell activating factor

Bcl-2:

B-cell lymphoma 2

Bcl-xL:

B-cell lymphoma-extra large

BCMA:

B-cell maturation antigen

BDNF:

Brain-derived neurotrophic factor

BM:

Bone marrow

BMSC:

Bone marrow stromal cells

COX-2:

CYCLOOXYGENASE-2

DEPTOR:

DEP domain containing MTOR-interacting protein

Dex:

Dexamethasone

DKK1:

Dickkopf-related protein 1

DVL:

Dishevelled

EGF:

Epidermal Growth factor

FGFR3:

Fibroblast growth factor receptor 3

FZD:

Frizzled

GSK3β:

Glycogen synthase kinase 3β

HGF:

Hepatocyte-growth factor

ICAM-1:

Intracellular adhesion molecule-1

IL-6:

Interleukin-6

IP10:

IFNgamma-inducible 10 kDa protein

I-TAC:

Interferon-inducible T-cell Alpha Chemoattractant

JNK:

C-Jun N-terminal kinases

KO:

Knock-out

LRP:

Low-density lipoprotein

MAF:

Musculoaponeurotic fibrosarcoma oncogene

MAPK-ERK:

Mitogen-activated protein kinase-extracellular signal regulated kinase

Mcl-1:

Myeloid leukemia sequence 1

MCP-1:

Monocyte chemotactic protein-1

MGUS:

Monoclonal gammopathy of undetermined significance

Mig:

Monocyte/macrophage-activating IFNγ-inducible protein

MIP-1α:

Macrophage inflammatory protein-1alpha

NF-κB:

Nuclear factor-kappa B

MMP:

Matrix metalloproteinases

NIK:

NF-κB inducing kinase

OPG:

Osteoprotegerin

OPN:

Osteopontin

PI3K:

Phosphoinositide 3-kinase

PKC:

Protein kinase C

PTGS2:

Prostaglandin-endoperoxide synthase

RANKL:

Receptor activator of nuclear factor kappa-B ligand

ROCK:

Rho-associated protein kinase

SDF-1α:

Stromal cell derived factor-1 alpha

SFRP:

Secreted frizzled related protein

SOCS:

Suppressors of cytokine signalling

STAT3:

Signal transducer and activator of transcription

TACI:

Transmembrane activator and calcium modulator and cyclophilin ligand interactor

TAK1:

Transforming growth factor activated kinase 1

TNF-α:

Tumor necrosis factor-alpha

TQ:

Thymoquinone

TRACP:

Tartrate-resistant acid phosphatise

TRAF:

TNF receptor associated factor

VCAM-1:

Vascular cell adhesion molecule-1

XIAP:

X-linked inhibitor of apoptosis protein

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Acknowledgments

This work was supported by NUS Bench to Bedside grant to GS. This work was also supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korean Ministry of Education, Science and Technology (MoEST) (No. 2011-0006220) to KSA. APK was supported by grants from the National Medical Research Council of Singapore [Grant R-713-000-124-213], Ministry of Education, Singapore [MOE2012-T2-2-139] and Cancer Science Institute of Singapore, Experimental Therapeutics I Program [Grant R-713-001-011-271].

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Authors and Affiliations

  1. Department of Pharmacology, Yong Loo Lin School of Medicine and Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117597, Singapore

    Sakshi Sikka, Muthu K. Shanmugam, Radhamani Kannaiyan, Rohit Surana, Alan Prem Kumar & Gautam Sethi

  2. Cancer Science Institute of Singapore, Centre for Translational Medicine, 14 Medical Drive, #11-01M, Singapore, 117599, Singapore

    Rohit Surana, Eun Myoung Shin, Alan Prem Kumar & Gautam Sethi

  3. School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley, WA, Australia

    Alan Prem Kumar

  4. Department of Biological Sciences, University of North Texas, Denton, TX, USA

    Alan Prem Kumar

  5. Department of Korean Pathology, College of Korean Medicine, Kyung Hee University, 1 Hoegi-Dong Dongdaemun-Gu, Seoul, 130-701, Republic of Korea

    Kwang Seok Ahn

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  1. Sakshi Sikka
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  2. Muthu K. Shanmugam
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  7. Gautam Sethi
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Correspondence to Gautam Sethi or Kwang Seok Ahn.

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Sikka, S., Shanmugam, M.K., Kannaiyan, R. et al. Suppression of essential pro-inflammatory signaling pathways by natural agents for the therapy of Multiple Myeloma. Phytochem Rev 13, 79–106 (2014). https://doi.org/10.1007/s11101-013-9287-3

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  • DOI: https://doi.org/10.1007/s11101-013-9287-3

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