B-Cell Disorders and Curcumin

Abstract

Clinical studies with patients with early hematological malignancies (ie, monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or stage 0/1 chronic lymphocytic leukemia) suggest that early intervention with curcumin, derived from the spice turmeric, may lead to prolonged survival and delay in progressive disease in some of these patients.

Curcuma longa or turmeric is a tropical plant native to southern and southeastern tropical Asia. It is a perennial herb belonging to the ginger family. The most active component in turmeric is curcumin. ¹ Curcumin has been extensively studied over the past 4 decades for its potential anti-inflammatory and/or anticancer effects. Curcumin has been found to suppress initiation, progression, and metastasis of a variety of tumors. ² These anticancer effects are predominantly mediated through its negative regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases, and other oncogenic molecules. It also inhibits proliferation of cancer cells by arresting them at different phases of the cell cycle and/or by inducing their apoptosis. ²

Cancers of the blood, which include lymphocyte and plasma cell malignancies, constitute a wide spectrum of different morphologic and clinical syndromes. Lymphocyte neoplasms can originate from cells that are at a stage prior to T- and B-lymphocyte differentiation from a primitive stem cell or from cells at stages of maturation after stem cell differentiation. Thus, acute lymphoblastic leukemias arise from an early lymphoid progenitor cell that may give rise to cells with either B- or T-cell phenotypes. On the other hand, chronic lymphocytic leukemia (CLL) arises from a more mature B-lymphocyte progenitor and multiple myeloma (MM) from progenitors at even later stages of B-lymphocyte maturation. ³

Multiple myeloma is a progressive, neoplastic disease and is characterized by high bone turnover, significant bone loss and pathological fractures resulting in significant morbidity and a high mortality. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic plasma cell disorders that can progress to MM. Recent studies have indicated that almost all cases of MM are preceded by a precursor state of MGUS or SMM. ⁴ Both MGUS and SMM represent a suitable model for studying multiple myeloma precursor disease, and to develop nontoxic early intervention strategies. ⁴ While MGUS is largely considered a benign condition, a number of studies have shown that patients with MGUS are at increased risk of high bone turnover and fractures even before progression to myeloma.^5-9 SMM accounts for about 15% of all the patients with newly diagnosed MM. ¹⁰ The risk of progression to symptomatic MM is markedly higher in SMM compared with MGUS, 10% per year versus 1% per year, respectively. ¹¹ Despite these findings, the cornerstone of managing multiple myeloma precursor disease involves a “watch and wait” strategy.

In vitro studies by Bharti et al^12,13 showed that curcumin suppresses proliferation and induces apoptosis in MM cells through the downregulation of interleukin-6 and nuclear factor-κB (NF-κB) and inhibits osteoclastogenesis through the suppression of RANKL signaling. Based on these antimyeloma effects of curcumin in vitro and the fact that this nonnutritive phytochemical is pharmacologically safe, even at doses as high as 8 g/d.^14,15 clinical studies were carried out at St George Hospital and Southern Sydney Haematology, Kogarah, Sydney from 2010 until 2015 and found that curcumin decreases paraprotein load, bone turnover, free light chains and % plasma cells in the bone marrow of some MGUS and SMM patients.^16-19

In addition, based on the demonstrable effects of curcumin in MGUS and SMM, curcumin was administered to a patient with IgG lambda SMM with supraglottic AL amyloidosis. Immunoglobulin light chain amyloidosis (AL) along with MM, SMM, and MGUS represent a spectrum of plasma cell dyscrasias (PCDs). In this patient, we demonstrated the beneficial effects of curcumin on the size of his laryngeal amyloid deposit after 5 years of curcumin therapy. ²⁰

For these patients with PCDs, a low risk of disease progression, the potential for drug-related toxicity and the failure to achieve a complete remission does not justify conventional chemotherapy as a therapeutic option.

Similarly, treatment of unselected early-stage CLL patients with chemotherapy is associated with increased toxicity and no increase in survival.^21,22 CLL is the most common type of leukemia in the Western world. ²³ It involves mature-appearing defective neoplastic lymphocytes (almost always B cells) with an abnormally long life span. The peripheral blood, bone marrow, spleen, and lymph nodes undergo leukemic infiltration. Nonspecific symptoms include fatigue and malaise and are usually attributable to the anemia. Clinical signs include lymphadenopathy, splenomegaly, and hepatomegaly. Diagnosis is confirmed by examination of peripheral smear and bone marrow aspirate. Patients with CLL have been shown to have elevated T cell (CD3, CD4, and CD8) and natural killer (NK) cell populations. ²⁴ A higher number of T and NK cells have been associated with delayed disease progression and time to treatment. ²⁵

There is no published intervention that alters the course of disease for patients with early stage CLL, that is, stage 0 or 1 disease (Rai staging system). ²⁶ These patients are usually monitored and commence therapeutic intervention if there is disease progression. This approach may often lead to patient’s anxiety. These patients represent an excellent cohort to evaluate the efficacy of nutraceutical agents (with a favorable toxicity) for disease prevention or delay in disease progression.

Curcumin has been shown to be a potent cytotoxic agent for primary CLL B cells by inhibiting specific prosurvival pathways such as STAT3, AKT, and NF-κB. ²⁷ Moreover, curcumin also suppresses the expression of the anti-apoptotic proteins Mcl-1 and X-linked inhibitor of apoptosis protein (XIAP), and upregulates the pro-apoptotic protein BIM. A combination of green tea extract and curcumin selectively upregulates STAT3 protein and its phosphorylation status when administered in co-culture of CLL B cells with stromal cells, while curcumin alone is able to overcome the stromal-induced protection when administered with epigallocatechin-3 gallate in a sequential fashion. ²⁸ These data suggested a potential therapeutic role for curcumin in the treatment of stage 0/1 CLL. Based on these studies and the safety and efficacy of this compound in patients with MGUS/SMM, we administered curcumin as Meriva, a standardized mixture of natural curcuminoids and lecithin in a 1:2 ratio.^29,30 to 21 individuals with stage 0/1 CLL to determine (a) its effect on absolute lymphocyte count and (b) whether any observed effect could be mediated by the numbers of CD4, CD8, and NK cells. The results of this 6-month study ³¹ suggest that a small percentage of patients with early CLL may derive benefit from curcumin therapy by decreasing their absolute lymphocyte count, perhaps through stimulating an immune response by increasing CD4, CD8, and NK cells. CD8 cytotoxic T lymphocytes are involved in antigen-specific tumor destruction and CD4 T cells are essential for helping the CD8 T cell-dependent tumor eradication.

Taken together, our studies with patients with early hematological malignancies (ie, MGUS, SMM, or stage 0/1 CLL) suggest that early intervention with curcumin may lead to prolonged survival and delay in progressive disease in some of these patients. Curcumin does not have long-term toxicities as evidenced by the number of patients with stable disease who have been taking curcumin for more than 5 years. Larger studies are warranted to assess its benefits in early hematological malignancies.