Methyl Sulfone Induces Loss of Metastatic Properties and Reemergence of Normal Phenotypes in a Metastatic Cloudman S-91 (M3) Murine Melanoma Cell Line

Abstract

BackgroundThe most deadly form of cancer is not lung or colon, breast or prostate; it is any cancer that has become metastatic. Mortality due to metastatic melanoma, one of the most aggressive and deadly cancers, has increased steadily over the last several decades. Unfortunately, the arsenal of chemotherapeutic agents available today is most often unsuccessful at extending and improving the life expectancy of afflicted individuals. We sought to identify an effective and nontoxic agent against metastatic melanoma.Methodology/Principal FindingsWe chose to study Cloudman S-91 mouse melanoma cells (sub-clone M3, CCL53.1) because these cells are highly aggressive and metastatic, representing one of the deadliest types of cancer. Melanoma cells also had an experimental advantage because their morphology, which is easily monitored, relates to the physiology of metastatic cells and normal melanocytes. We chose to test methyl sulfone as a chemotherapeutic agent for two reasons. Because of its chemical structure, we speculated a potential anti-cancer activity by targeting microtubules. Equally important, methyl sulfone has a well-established safety profile in humans. Surprisingly, we found that malignant melanoma cells exposed to methyl sulfone demonstrated the loss of phenotypes characteristic of malignant cells, and the reemergence of phenotypes characteristic of healthy melanocytes. Briefly, over time methyl sulfone induced contact inhibition, loss of ability to migrate through an extracellular matrix, loss of anchorage-independent growth, proper wound healing followed by contact inhibition, irreversible senescence followed by arborization with melanosomes in arbors as seen in normal melanocytes.Conclusions/SignificanceMethyl sulfone may have clinical potential as a non-toxic agent effective against metastatic melanoma. Additionally, methyl sulfone has promise as a tool to explore molecular mechanisms of metastatic transformation as well as fundamental processes such as cell migration, contact inhibition, wound healing and cellular senescence.

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“…Interestingly, this is the same effective concentration of methyl sulfone that we found for the metastatic melanoma cell line Cloudman S-91 (subclone M3) [11]. Similarly, Layman [20] found that 200 m M methyl sulfone induced growth arrest in cultures of aortic smooth muscle cells and aortic endothelial cells without causing cell death.…”

“…These data suggest that methyl sulfone may have induced a separation between structure and function. These data further suggest that methyl sulfone may have induced differentiation, as we found in melanoma cells [11]. Along these lines, methyl sulfone is a metabolite of dimethyl sulfoxide (DMSO), and it has been shown that DMSO induces differentiation of leukemic erythroid cells along the erythroid pathway.…”

“…In support of this hypothesis, we found that methyl sulfone generates antimetastatic cancer activity against a cell line of malignant melanoma [11]. In addition, Lim et al [12] showed recently that methyl sulfone induced cell growth arrest in several breast cancer cell lines.…”

“…Methyl sulfone interested us initially because its chemical structure suggested anticancer activity [11]. In support of this hypothesis, we found that methyl sulfone generates antimetastatic cancer activity against a cell line of malignant melanoma [11].…”

GC/MS analysis and In-vitro Antioxidant activity of methanol extract of Ulothrix flacca and its main constituent Dimethyl Sulfone.

“…Dimethyl sulfone decreases arthritis pain and improves physical function of osteoarthritis human knees without major adverse events [24]. This compound has also been found to be effective for treating allergies [25], osteoarthritis pain [26], inflammation [27], repetitive stress injuries [28], and bladder disorders like intestinal cystitis [29]. Dimethyl sulfone can induce wound healing, contact inhibition, and can block the ability of cells to migrate through the extra-cellular matrix.…”