The Rationality of Implementation of Dimethyl Sulfoxide as Differentiation-inducing Agent in Cancer Therapy
1Nimni-Cordoba Tissue Engineering and Drug Discovery Lab, Department of Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA, U.S.A.
2Department of Translational Research, Western University of Health Sciences, Pomona, CA, U.S.A.
3Department of Oncology, National Children Hospital of Vietnam, Hanoi, Vietnam
4Department of Traumatology, National Institute of Ophthalmology of Vietnam, Hanoi, Vietnam
5Integrated Medical Associates, Foster City, CA, U.S.A.
6Thai Minh Pharmaceutical JSC, Hanoi, Vietnam
Differentiation is the cellular developmental process whereby cells change in form and develop specialized functions. The tumor cell differentiation stage is a crucial aspect of defining histopathological malignancies. The differentiation process is typically unidirectional in normal cells; however, cancer cells, like stem cells, have shown that this process can be reversible, be dedifferentiated or re-differentiated. Higher degrees of differentiation pose a better prognosis than a low degree and are strongly associated with tumor behavior, invasiveness, and resistance to cancer therapy (1).
Treating cancers through the induction of cell differentiation has been an attractive and practical approach (2). Reagents, such as all-trans-retinoic acid (ATRA), nerve growth factor (NGF), dimethyl sulfoxide (DMSO), vitamin D3, 12-0-tetradecanoylphorbol 13-acetate (TPA), peroxisome proliferator-activated receptor-gamma (PPAR-γ), hexamethylene-bis-acetamide (HMBA), transforming growth factor-beta (TGF-β), butyric acid, cAMP, and vesnarinone, have been extensively studied for their differentiation-inducing ability on cancer cells in
A potential chemical of interest that fits this bill is Dimethyl sulfoxide (DMSO). As an amphipathic agent, DMSO is widely used as a solvent for water-insoluble molecules, cryopreserving agents, and cell therapies (12). It has been used as a cell differentiation inducer, free radical scavenger, and radioprotectant (13-15). In addition, various pharmaceutical and therapeutic properties of DMSO, such as anti-inflammatory, antiviral, antifungal, antibacterial, local, and systemic analgesia, and membrane penetration enhancement, have been applied in preclinical applications (16,17). DMSO is used as a drug delivery vehicle for various human and animal conditions, including gastrointestinal diseases, amyloidosis, dermatological disorders, traumatic musculoskeletal disorders, brain edema, rheumatologic diseases, soft tissue injuries of chemotherapeutic drugs, and radiotherapy (18-25). FDA has approved DMSO for treating interstitial cystitis in the United States (26).
Previously, our group reported the excellent safety profile and efficacy of DMSO for palliative care and pain control in advanced cancer patients (27-30)
In this current review, we summarize experimental and clinical evidence to support the implementation of DMSO as a safe, effective, and affordable differentiation inducer to potentiate the efficacy of cancer therapeutic modalities.
Peripheral blood leukocytes from a patient with APML are predominantly promyelocytes. When DMSO was added in the culture medium, cells were induced to differentiate into mature types of granulocytes, including myelocytes, metamyelocytes, and segmented neutrophils. All 150 clones developed from the HL-60 culture showed similar morphological differentiation with functional maturity, causing leukemic cells to lose their proliferative properties in the presence of DMSO (36). The induction of leukemic cell differentiation into mature cells is a major strategy for treating leukemia. Since differentiated leukemic cells lose their proliferative and tumor-forming abilities, different differentiation inducers have been extensively studied as valuable candidates for leukemia treatment. The study by Hong-Nu
In another study, the same group of researchers demonstrated that DMSO induced up-regulation of the tumor suppressor PTEN by activating NF-kB (38). It is proposed that the degradation of phosphatidylinositol 3,4,5-trisphosphate (PIP3) to phosphatidylinositol 4,5-bisphosphate inhibits the activity of PI3K. PIP3 is an essential regulator of cell growth and survival through Akt, expressed in HL60 cells (39). Cancer survival signals are mediated mainly by PI3K/Akt (40); hence this pathway may contribute to a resistant phenotype. Therefore, an increased expression of the tumor suppressor PTEN could lead to the inhibition of Akt phosphorylation, allowing HL60 cells to differentiate into neutrophil-like cells.
The highly aggressive prostate cancer cells utilize androgen receptor (AR) to signal their growth and metastasis. Despite the treatment advancement achieved through androgen deprivation therapy, the recurrence of castration-resistant prostate cancer (CRPC) cannot be prevented. DMSO has been shown to suppress AR levels in the CRPC cell lines by decreasing the expression of hetero-nuclear ribonucleoprotein H1 (41). Treatment with low dose DMSO (0.1-1%) did not exhibit any cytotoxicity or changes in cell viability; minimal cytotoxicity was observed when DMSO concentration increased to 2.5% in a 96-h treatment. These clinical doses of DMSO caused a significant (
Low-dose DMSO significantly enhanced the antiproliferative effect of interferon-alpha (IFN-α) in several human lung adenocarcinoma cells
DMSO and butyrate were studied for their effects on four human intestinal tumor cell lines
The most attractive potential application of DMSO in cancer treatment is as an adjuvant in immunotherapy. Jiang
In the hepatocellular carcinoma cell line Huh7, regular culture in the absence of DMSO initially formed tightly packed monolayers, but was compromised on day 10 with extensive cell death (50). In the presence of 1% DMSO, the monolayers were composed of mono- and binucleated cells with primary hepatocytes features. The addition of DMSO has been shown to significantly increase the expression of three hepatocellular differentiation markers, including human albumin, A1AT mRNA, and HNF4-a (50). In a subsequent study, Huh7 cells treated with DMSO had increased ability to metabolize drugs, as evidenced by increased levels of various drug-metabolizing enzymes (51). Additionally, DMSO exposure inhibits cell division, arrests the cell cycle in G0/G1 state, remaining viable in culture without splitting for over 60 days, and increases cell differentiation characterized by an increase in liver-specific genes (51).
The above experimental research indicates a robust differentiation-inducing activity of DMSO in different cancer cell lines, suggesting a possible practical application of this already approved pharmaceutical solvent, cryoprotectant, and drug as adjuvant therapy in conventional cancer treatment.
Regarding dermatological side effects, the most reported symptoms related to topical application are rash, dry skin, and contact dermatitis. However, the reactions are usually mild and brief and do not re-appear with conditional treatment (60). When comparing adverse event rates, there was no difference between the trial DMSO drug, placebo, or DMSO vehicle when looking at the skin, gastrointestinal, or cardiac events (61). No cases of lens changes in humans have been reported with prolonged administration of large amounts of DMSO in systemic, topical, or local ophthalmic treatment (62). Therefore, DMSO was proven to have little to no toxicity when used in clinically adequate doses. The pharmacological safety profile of DMSO is listed in
For the past two decades, the registration number of DMSO-based pharmaceutical agents, over-the-counter (OTC) drugs, and medical devices (31) has increased globally. The application of DMSO as an active ingredient or excipient in drug formulations has expanded to topical, oral, and parenteral products (63). DMSO (10%) is commonly used as a cryoprotective agent (CPA), added to the culture media for preserving and storing biological tissues (64). It acts as a penetrating cryopreservation agent to increase the porosity of the cellular membrane, allowing water to flow more freely through the membrane, avoiding ice crystal formation (65). DMSO has remained the gold standard CPA for many different cell types over other agents such as glycerol and polyethylene glycol (66). FDA has approved DMSO as a CPA for sperm, eggs, stem cells, bone marrow cells, and organs for transplant (16). In the concentration ranging from 5% to 17%, DMSO is a critical CPA in many cell therapy products, such as CAR-T, melanoma treatment Mekinist, and stem cell transplantation (31).
Discussion and Perspectives
DMSO is a very versatile compound that is currently widely used in tissue/organ preservation and as a cryoprotectant for biologic therapy. There is also a huge potential for medical uses of DMSO in cancer management, including penetration-enhancing and solvent excipients in cancer therapeutics, pain control, palliative care, and treatment of tissue injuries due to radiotherapy and chemotherapy. Numerous experimental and clinical data suggest a possible productive role of DMSO as an active drug or adjuvant therapeutic agent to improve the effectiveness of existing cancer therapies and control abnormal cell differentiation, in particular inhibition of end-cell differentiation, in tumors (67).
Based on the available published research data, DMSO might be implemented as an effective, safe, and inexpensive differentiation-inducing therapeutic agent to enhance the overall efficacy of the established conventional and complementary cancer treatments. Besides the documented robust differentiation-inducing activities, DMSO has also demonstrated several anti-cancer properties that could further benefit cancer patients, including suppressing proliferation and inducing apoptosis (68-70).
Although clinical research on DMSO has regained some enthusiasm in the past 20 years, the development of DMSO as an active pharmaceutical drug or adjuvant therapeutic has not been attractive to the pharmaceutical industry, mainly because of its generic status. DMSO will remain as an important component in the most sophisticated modern cell therapeutics in stem cell transplantation and immunotherapy. Currently, DMSO is widely used in various pharmaceutical preparations to enhance the solubility of drugs, leading to the delivery of a higher concentration of medication to the targets (71).
Since DMSO is inexpensive and non-patentable, pharmaceutical companies lack the financial incentive to develop this therapeutic agent in cancer clinical applications. Future non-profit and doctors-driven explorative and translational clinical investigations are needed to prove and promote the practical implementation of DMSO as a possible adjuvant drug, analgesic, and palliative care therapy for cancer patients.
Conflicts of Interest
No competing financial interests exist in relation to this study.
All Authors contributed equally to the writing and submission of the manuscript.