Manipulation of cellular redox parameters for improving therapeutic responses in B-cell lymphoma and multiple myeloma

Free Radical and Radiation Biology Program, Department of Radiation Oncology, The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242, USA.
Journal of Cellular Biochemistry (Impact Factor: 3.26). 02/2012; 113(2):419-25. DOI: 10.1002/jcb.23387
Source: PubMed


Developing novel combined-modality therapeutic approaches based on understanding of the involvement of redox biology in apoptosis of malignant cells is a promising approach for improving clinical responses in B-cell lymphoma and multiple myeloma. Therapeutic modalities that generate reactive oxygen species (i.e., radiation, photodynamic therapy, and specific chemotherapeutic drugs) have been shown to be selectively cytotoxic to malignant B-cells. In this review, we will discuss agents that induce apoptosis in B-cell tumors by oxidative stress. Subsequently, a novel biochemical rationale (based on fundamental differences in cancer vs. normal cell oxidative metabolism) for combining oxidative stressors with radiotherapy and chemotherapy, that may lead to designing of more effective treatment strategies for B-cell malignancies, will be discussed. Besides providing potential curative benefit, such novel therapies could also selectively target and inhibit the emergence of drug-resistance in tumor cells, which is a major determinant of treatment failure in many B-cell malignancies.

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    • "In comparison with normal tissues, cancer cells thrive in a pro-oxidant environment and are tolerant to oxidative stress [6]. Indeed, MM patients show increased lipid peroxidation and lower levels of antioxidant enzymes in plasma and erythrocytes [7–10]. MnSOD [manganese SOD (superoxide dismutase)] plays a major role in maintaining cellular antioxidant capacity [11,12]. "
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    ABSTRACT: IL (interleukin)-6, an established growth factor for multiple myeloma cells, induces myeloma therapy resistance, but the resistance mechanisms remain unclear. The present study determines the role of IL-6 in re-establishing intracellular redox homoeostasis in the context of myeloma therapy. IL-6 treatment increased myeloma cell resistance to agents that induce oxidative stress, including IR (ionizing radiation) and Dex (dexamethasone). Relative to IR alone, myeloma cells treated with IL-6 plus IR demonstrated reduced annexin/propidium iodide staining, caspase 3 activation, PARP [poly(ADP-ribose) polymerase] cleavage and mitochondrial membrane depolarization with increased clonogenic survival. IL-6 combined with IR or Dex increased early intracellular pro-oxidant levels that were causally related to activation of NF-κB (nuclear factor κB) as determined by the ability of N-acetylcysteine to suppress both pro-oxidant levels and NF-κB activation. In myeloma cells, upon combination with hydrogen peroxide treatment, relative to TNF (tumour necrosis factor)-α, IL-6 induced an early perturbation in reduced glutathione level and increased NF-κB-dependent MnSOD (manganese superoxide dismutase) expression. Furthermore, knockdown of MnSOD suppressed the IL-6-induced myeloma cell resistance to radiation. MitoSOX Red staining showed that IL-6 treatment attenuated late mitochondrial oxidant production in irradiated myeloma cells. The present study provides evidence that increases in MnSOD expression mediate IL-6-induced resistance to Dex and radiation in myeloma cells. The results of the present study indicate that inhibition of antioxidant pathways could enhance myeloma cell responses to radiotherapy and/or chemotherapy.
    Full-text · Article · Jun 2012 · Biochemical Journal
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    • "Our increased understanding of the role of endogenous and therapy-induced oxidative stress, which results from an imbalance in the production of reactive oxygen species (ROS) and cellular antioxidant defenses, offers a biochemical rationale for designing novel ways to induce oxidative stress-mediated killing of cancer cells while sparing healthy tissues (Gius and Spitz, 2006; Goel et al., 2011; Spitz et al., 2004). Below are few cytotoxic agents that have been shown to induce ROS-mediated anti-myeloma activity. "

    Full-text · Chapter · Mar 2012
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    ABSTRACT: Multiple myeloma (MM) is a malignant neoplasm of plasma cells that constitutes 1% of all cancers and 10% of hematologic neoplasms. MM is the second most common hematologic malignancy after non-Hodgkin's lymphoma. It is estimated that 21,700 new cases of MM (ap-proximately 12,190 men and 9,510 women) will be diagnosed during 2012 in the United States, and approximately 10,710 individuals (6,020 men and 4,690 women) will die of the disease [1]. The five-year survival rate for patients with MM is 40%, with younger patients showing high-er survival rates than the elderly. However, MM still remains incurable and emergence of drug-resistance is considered to be one of the major causes of relapsed or refractory disease. Research in the last decade has shed new light on the biology of MM and the importance of the bone marrow microenvironment in supporting MM cell growth, survival, and therapy resistance. In addition, significant insight has been gained into the role of natural killer (NK) cells in myeloma progression and the existence of MM cancer stem cells (CSCs) has been established. Hence, with increased understanding of the MM disease and a novel armamentarium of molecularly targeted therapeutic agents, are we are close to overcoming the challenge of relapse in MM? Traditionally, chemotherapy of MM has included corticosteroids (i.e. dexamethasone and prednisone) and cytotoxic drugs (i.e. melpha-lan, vincristine, cyclophosphamide, and doxorubicin). The mainstay high-dose standard treatment protocol for MM patients is comprised of induction therapy with vincristine, doxorubicin, and dexamethasone (VAD) followed with autologous stem cell transplantation. In recent years, the response rates and survival of MM patients have substantially improved with the introduction of novel agents such as lenalidomide, and bortezomib [2]. Based upon the biochemical rationale that relative to normal cells cancer cells intrinsically experience oxidative stress, re-searchers have combined oxidative stressors (certain chemotherapeu-tic drugs and radiation therapy) with agents that deplete intracellular antioxidants, inhibit antioxidant enzyme activity, and/or disrupt mito-chondrial membrane potential [3]. To selectively eliminate myeloma cells by oxidative catastrophe, few cytotoxic drugs hypothesized to act via reactive oxygen species-induced oxidative stress (i.e. arsenic triox-ide, dexamethasone, bortezomib) have been combined with agents that deplete intracellular antioxidants (i.e. buthionine sulfoximide, ascorbic acid), inhibit antioxidant enzyme activity (i.e. 2-methoxyestradiol), in-hibit the secretion of pro-proliferative cytokines (i.e. IL-6 by dexameth-asone), and/or other cytotoxic drugs that disrupt mitochondrial mem-brane potential to release cytochrome c (i.e. bortezomib and farnesyl transferase inhibitors) [4]. Radiation therapy is a powerful treatment modality for MM, yet the use of radiotherapy in MM has been mainly limited to palliative care or myeloablative pre-conditioning regimens [5]. Recently, stud-ies utilizing targeted radiotherapeutic methods such as radioimmuno-therapy [5,6], radiovirotherapy [7,8], and bone-seeking radiopharma-ceuticals [9,10] have extended the use of ionizing radiation for therapy of systemic MM. Furthermore, combining targeted radiotherapy with radiation-sensitizing chemotherapeutic drugs such as bortezomib [11-13] and dexamethasone [14] can provide additional benefit by improv-ing the overall treatment efficacy in MM. The bone marrow microenvironment plays an active role in sup-porting tumor growth, angiogenesis, bone disease, and drug resistance in MM [15]. Of the various secreted cytokines, paracrine and autocrine regulation by interleukin (IL)-6 plays a particularly important role in emergence of chemoresistance and radioresistance in MM. In a recent study, we reported a correlation between nuclear factor-κB-dependent manganese superoxide dismutase expression and IL-6-induced my-eloma cell resistance to dexamethasone and radiation [16]. Thus, one may perceive that novel preclinical studies involving the inhibition of antioxidant pathways may have the potential to enhance myeloma cell responses to radiotherapy and/or chemotherapy. MM progression has been associated with immune dysregulation, thus novel therapeutic strategies that would augment NK cell function are being tested in MM [17]. In many tumors types, such as hepatocel-lular carcinoma, breast cancer, and medulloblastoma, a sub-population of self-renewing cells known as cancer stem cells (CSCs) has been es-tablished. Since CSCs are particularly resistant to radiotherapy and chemotherapy, novel strategies that target both CSCs and bulk tumor populations can potentially provide improved cure rates of cancer [18]. Recent progress suggests a CD138 -/CD19 + /CD20 + /CD27 + phenotype for myeloma CSCs. Myeloma CSCs have been shown to be resistant to dexamethasone, cyclophosphamide, and bortezomib but lenalidomide has been shown to target and kill a sub-population of myeloma CSCs. Therapeutic strategies that can target and eliminate CSCs in addition to differentiated myeloma cells have the potential to alleviate therapy resistance challenge faced by the current clinical treatments in MM. In summary, with increased understanding of MM disease progres-sion and the emergence of therapy resistance, we are ready to design and test novel preclinical and clinical combination therapy protocols involving molecularly targeted chemotherapeutic drugs and oxidative stress inducing agents that may offer improved response rates for MM patients.
    Full-text · Dataset · Jan 2012
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