A Review of The Synergistic Effects of Curcumin with Proteasome Inhibitors in Multiple Myeloma Preclinical Models

Abstract

Proteasome inhibitors are the cornerstone of multiple myeloma treatment, but challenges still remain despite the increased survival rates. We conducted a review on the role of curcumin, a natural product, as an adjunct to bortezomib and carfilzomib in preclinical multiple myeloma models. Four studies reviewed showed enhanced anticancer effects when curcumin was combined with bortezomib compared to either treatment alone. Two additional studies showed similar results with carfilzomib. Synergistic mechanisms include inhibition of NF-kB, IL-6-induced signaling pathways, JNK pathway modulation, and increased cell cycle arrest.

Introduction

Multiple myeloma (MM) is a neoplasm of plasma cells. Normal plasma cells play the role of producing antibodies as part of the immune system. In MM, the plasma cells behave abnormally and proliferate rapidly, cluster together in the bone marrow, and produce excess antibodies often causing organ damage including kidney injury, hypercalcemia, anemia, and bone lesions. ¹ Incidence of MM has increased globally over the last few decades, and makes up approximately 17% of hematologic malignancies, despite the various new treatment options which have been developed. ² Proteasome inhibitors are included in many treatments with improved response rates. ³ Proteasome inhibitors, starting with the first-generation drug bortezomib, have been in clinical practice for approximately 2 decades, with improved progression free and overall survival rates when combined with different classes of medications over the years. ⁴ Normally, proteasomes function as multi-unit systems in cells to degrade proteins; bortezomib and carfilzomib inhibit this function, leading to cellular dysregulation and apoptosis especially in MM cells, which are sensitive. ⁵

Therapies in MM commonly include combinations of proteasome inhibitors (eg, bortezomib, carfilzomib, ixazomib), immunomodulatory agents (eg, lenalidomide, pomalidomide), steroids (eg, dexamethasone), immunotherapy (eg, monoclonal antibody therapy, chimeric antigen receptor T-cell therapy, bispecific T-cell engager therapy), traditional chemotherapy, and autologous stem cell transplant. ⁶ Although these therapies have led to increased survival, the challenges of disease relapse or refractory disease remain. Symptom burden including pain, fatigue, and anxiety is especially worsened with relapsed disease states. ⁷ MM cells often develop resistance to proteasome inhibition through specific mutations, heat-shock proteins, drug efflux, and alternate signaling pathways. ⁸ Additionally, there are toxicities associated with proteasome inhibitors. These toxicities include peripheral neuropathy, thrombocytopenia, herpes zoster reactivation, and other end-organ complications. ⁹ Limited evidence is available for patients seeking other safe, integrative therapies to potentiate the effects of current therapies, control their side effects, or control symptoms of disease.

Curcumin is a natural phenol derived from Curcuma longa, or turmeric, which has been commonly used in Asia for centuries. ¹⁰ Curcumin has known antioxidant and anti-inflammatory effects, demonstrated in several chronic clinical conditions, as well as proposed anticancer activity through modulation of various pathways and cytokines.^11,12 Its use has shown promise in preclinical studies involving multiple malignancies including breast, colon, and prostate cancer, though limited number of clinical studies have yet to show the same response consistently. ¹³ A recent study utilizing curcumin as part of combination therapy with proteasome inhibitors and/or immunomodulatory drugs in a series of patients intolerant of dexamethasone showed decrease in paraprotein load and plasmacytosis. ¹⁴

There is limited evidence available for the use of curcumin in combination with standard MM therapies, especially with previously described combinations including proteasome inhibitors. Curcumin has been shown to have anti-myeloma effects independently, ¹⁵ as well as synergistic effects with proteasome inhibitors in cell cultures. ¹⁶ A recent review by Ding et al ¹⁷ showed synergistic effects of bortezomib with various flavonoids and non-flavonoids, including curcumin, in multiple preclinical models. Our review is not limited to bortezomib only and utilizes a different search formula specific to bortezomib and carfilzomib. This review aims to specifically explore the synergistic mechanisms of anticancer effects of curcumin in combination with bortezomib and carfilzomib in the treatment of MM.

Methods

A literature review was conducted on PubMed using the key terms “bortezomib” AND “curcumin” AND “multiple myeloma” or “carfilzomib” AND “curcumin” AND “multiple myeloma.” Inclusion criteria included any study from 2006 to 2021 using a combination of curcumin with bortezomib or carfilzomib in MM preclinical models (in vitro or in vivo). International studies were also included. Studies which only included curcumin monotherapy or did not combine curcumin with bortezomib or carfilzomib, studies not specific to MM cell lines/models, and not available as full articles were excluded (Figure 1).

Figure 1.

Flow diagram outlining the literature review and study retrieval.

Results

A total of 17 studies resulted from the initial query. Of these, 6 studies met inclusion criteria; 2 additional studies were excluded due to their lack of availability as full articles. Four of the 6 included studies consisted of bortezomib in combination with curcumin, while 2 of the 6 studies evaluated a combination of carfilzomib with curcumin (Table 1).

Table 1.

Summary of Preclinical Studies Using Curcumin in Combination With Proteasome Inhibitors Bortezomib and Carfilzomib.

Authors, Journal	Study design	Treatment	Synergistic effect
Bai and Zhang 18 , Int J Mol Sci. 2012	In vitro (multiple myeloma H929 cells)	Curcumin and bortezomib	- Increased apoptosis, NF-kB downregulation, JNK pathway modulation
Mujtaba et al 19 , Int J Mol Med. 2012	In vitro (Arp cell line)	Curcumin and bortezomib	- Increased apoptosis, cytotoxicity, and proteasome inhibition with water-soluble curcumin analogs (especially #12)
Park et al 20 , Mol Oncol. 2008	In vitro (multiple myeloma U266 cells)	Curcumin and bortezomib	- Increased apoptosis, cytotoxicity, and inhibition of IL-6-induced signaling pathways including JAK/STAT
Sung et al 21 , Mol Cancer Ther. 2009	In vitro (U266, chemo-resistant cell lines) and in vivo (mice)	Curcumin and bortezomib	- Increased apoptosis and NF-kB inhibition
			- Enhanced tumor volume reduction, NF-kB inhibition, decreased Ki-67, VEGF, and microvessel density in mice
Banerjee et al 22 , Proc Natl Acad Sci USA. 2018	In vitro (MM.1S, MM.1R cell lines)	Curcumin and carfilzomib	- Enhanced cytotoxicity, apoptosis
Allegra et al 23 , Toxicol In Vitro. 2018	In vitro (multiple myeloma U266 cells)	Curcumin and carfilzomib	- Enhanced apoptosis, NF-kB downregulation, p53/p21 upregulation, increased cell cycle arrest G0/G1 phase

Pro-Apoptosis Synergistic Effects of Curcumin With Proteasome Inhibitors

All 4 in vitro studies with combination of bortezomib and curcumin showed increased apoptosis and enhanced inhibition of cell proliferation than either bortezomib or curcumin alone.^18-21 Both studies including carfilzomib in combination with curcumin showed increased cytotoxic and pro-apoptotic effects than either agent alone in various MM cell lines.^22,23

Synergistic Mechanisms of Curcumin and Proteasome Inhibitors

Bai and Zhang ¹⁸ showed significant decrease in NF-kB activation in H929 MM cells treated with curcumin and bortezomib combination. They also showed attenuation of apoptosis response to combination treatment when a JNK inhibitor was added, suggesting JNK modulation as part of the overall response. Water-soluble curcumin analogs had independent proteasome inhibitory effects, which in combination with bortezomib led to enhanced cytotoxic, antiproliferative, and pro-apoptotic effects on Arp MM cells. ¹⁹ Combined curcumin and bortezomib treatments stimulated apoptosis in MM cells by modulating IL-6-induced signaling pathways including JAK/STAT and MAPK, specifically by decreasing STAT3 and Erk phosphorylation. ²⁰

Sung et al ²¹ showed curcumin to independently decrease proliferation of various chemo-resistant MM cells, which were resistant to doxorubicin, dexamethasone, and melphalan. They showed significantly enhanced apoptosis and downregulation of NF-kB when curcumin was combined with bortezomib. Curcumin was also shown to suppress PI3K/AKT pathway, as well as downregulate bcl-2, cyclin D1, survivin, and VEGF. A combination of curcumin and carfilzomib showed downregulation of NF-kB activity, upregulation of p53 and p21, and increased cell cycle arrest in G0/G1 phase (Figure 2). ²³

Figure 2.

Synergistic effects of curcumin and proteasome inhibitors on pathways involved in MM cells.

Synergistic Effects of Curcumin and Bortezomib in Mice Models

In mice models, there was overall tumor reduction seen in mice treated with curcumin and bortezomib alone. ²¹ This tumor reduction effect was significantly enhanced in mice treated with combination of both. Tumor samples with combination treatments showed decreased NF-kB activation, Ki-67, VEGF expression and microvessel density.

Discussion

Despite recent advances in therapy, MM remains a challenging malignancy to treat, with multiple relapses requiring several lines of therapy. ²⁴ High symptom burden, including physical and psychological symptoms, often lead to significantly reduced quality of life. ²⁵ Limited evidence-based data exists for patients seeking additional therapeutic options to augment the current standards of care. Curcumin, a compound from turmeric, has been shown to induce apoptosis and autophagy, inhibit cell cycle progression and angiogenesis, and modulate cancer-specific pathways. ²⁶ This review suggests curcumin may have a therapeutic role in MM management. Preclinical studies show improved chemosensitivity and enhanced anticancer effects when curcumin is combined with proteasome inhibitors, such as bortezomib and carfilzomib. Curcumin appears to affect various pathways including NF-kB, JAK/STAT, VEGF, and cell cycle proteins (Figure 3).

Figure 3.

Synergism of proteasome inhibitors and curcumin.

Studies included in this review consistently demonstrate significantly improved synergistic effect with the addition of curcumin to proteasome inhibitor monotherapy. Evaluation of curcumin in clinical settings has shown safety and tolerability.^14,27 One small case series of MM patients (n = 15) who received 3 to 4 g oral curcumin daily along with proteasome inhibitors and/or immunomodulatory drugs for mean duration of approximately 6 years showed safety and good tolerability. ¹⁴ Diarrhea was reported as a potential side effect in 2 patients. Although decrease in paraprotein load and plasmacytosis were reported, it is unclear how much the addition of curcumin contributed to this compared to standard therapy. More recently, a randomized controlled trial with 33 transplant ineligible MM patients receiving melphalan, prednisone and curcumin (8 g oral daily) showed significantly increased remission and decrease in cytokines compared to melphalan, prednisone and placebo. ²⁸ Further randomized controlled trials with oral curcumin as an adjunct to proteasome inhibitors are necessary to evaluate for clinical efficacy.

This review has several limitations including the review itself being limited to studies queried in PubMed only, as well as overall differences amongst preclinical models. Studies in this review utilized different MM models (cell lines), and various curcumin formulations and dosages which were not standardized. Additionally, included studies analyzed different dependent variables such as effects on specific pathways, chemosensitivity, and overall tumor burden in vivo. This review was also limited to combination of curcumin with only 2 proteasome inhibitors, bortezomib and carfilzomib. Broader review with multiple databases may result in greater number of studies that meet inclusion criteria. There are other challenges, such as variability in the bioavailability of curcumin, which may further hinder translation to clinical application. Further research on developing novel curcumin analogs or other drug delivery systems to increase bioavailability may be necessary for broader clinical use.

Though not formally studied as a part of this review, curcumin has known anti-inflammatory effects and may have additional benefit in reducing some of the adverse effects of MM therapies in clinical settings. ²⁹ In a recent randomized controlled clinical trial, oral curcumin in addition to melphalan and prednisone showed improved insomnia at 4 months of treatment compared to melphalan, prednisone, and placebo. ³⁰ Curcumin may ameliorate overall physical symptom burden related to MM since it has been shown to improve quality of life and improve physical symptoms such as musculoskeletal pain.^31,32 Curcumin has also been shown to improve anxiety and depression symptoms in the general population, which often impact patients with MM especially in relapsed settings. ³³ Future clinical studies may be useful in addressing these additional symptomatic benefits of curcumin in MM patients.

Conclusion

Multiple myeloma is a challenging hematologic malignancy to treat due to frequent relapses requiring multiple lines of therapy. This review summarizes the synergistic anticancer effects of proteasome inhibitors when combined specifically with curcumin in preclinical models. It also demonstrates various pathways through which this synergistic effect may occur. Additional clinical studies with blinded, randomized controlled trials are needed to evaluate the safety and efficacy of oral curcumin as an integrative adjunct to proteasome inhibitors in treatment of multiple myeloma.