Cotylenin A and arsenic trioxide cooperatively suppress cell proliferation and cell invasion activity in human breast cancer cells

Abstract

Abstract. Arsenic trioxide (ATO) is an approved treatment for acute promyelocytic leukemia (APL). It has also shown potential for treatment of multiple myeloma and various solid tumors including breast cancer. The requirement of high, toxic concentrations for the induction of apoptosis in non-APL and solid tumor cells is a major limitation for its use in other hematological malignancies and solid tumors. We have examined whether inducers of differentiation of leukemia cells can control the growth of solid tumor cells. In the present study, we found that cotylenin A, a plant growth regulator and a potent inducer of differentiation in myeloid leukemia cells, significantly potentiated both ATO-induced inhibition of cell growth in a liquid culture, and ATO-induced inhibition of anchorageindependent growth in a semi-solid culture in human breast cancer MCF-7 and MDA-MB-231 cells. ISIR-005 (a synthetic cotylenin A-derivative) was also able to enhance ATO-induced growth inhibition. The combined treatment with cotylenin A and ATO induced cleaved caspase-7 in MCF-7 cells at the concentrations which ATO alone scarcely induced and cotylenin A alone only weakly induced. Expression of survivin in MCF-7 cells was markedly decreased with the presence of both cotylenin A and ATO, although the expression of survivin was only slightly decreased by cotylenin A or ATO alone. The pretreatment with N-acetylcysteine significantly reduced the combination treatment-induced cell growth inhibition. These data suggest that induction of cleaved caspase-7, inhibition of survivin and oxidative responses are important events in the corporative inhibition in the growth of MCF-7 cells induced by both cotylenin A and ATO. Furthermore, we found that the combined treatment with cotylenin A and ATO also could be effective in suppressing the invasive capacity of MDA-MB-231 cells determined with the impedance-based xCELLigence Real-Time Cell Analysis technology. These results suggest that cotylenin A is an attractive enhancer for the ATO-induced anticancer activities in human breast cancer.

Piperlongumine rapidly induces the death of human pancreatic cancer cells mainly through the induction of ferroptosis

“…We recently reported that CN-A significantly potentiated the arsenic trioxide-induced inhibition of cell growth in human breast cancer cells (13). We found that this synergistic growth inhibitory effect of CN-A plus arsenic trioxide was significantly reduced by treatment with N-acetylcysteine (NAC), a typical ROS scavenger (13).…”

“…Cotylenin A (CN-A), which has a diterpenoid tricarbocyclic skeleton, is produced by plant-pathogenic fungi and has been shown to induce the differentiation of human myeloid leukemia cells and apoptosis or the growth arrest of human carcinoma cells in the presence of interferon-α or rapamycin, respectively (11,12). We recently reported that CN-A significantly potentiated the arsenic trioxide-induced inhibition of cell growth in human breast cancer cells (13). We found that this synergistic growth inhibitory effect of CN-A plus arsenic trioxide was significantly reduced by treatment with N-acetylcysteine (NAC), a typical ROS scavenger (13).…”

U937 cell apoptosis induced by arsenite is prevented by low concentrations of mitochondrial ascorbic acid with hardly any effect mediated by the cytosolic fraction of the vitamin

“…In a different perspective, an elevation in mitochondrial AA may instead lower the risk of toxicity in individuals environmentally or occupationally exposed to arsenic. Future studies will determine the impact of mitochondrial AA on the lethal response mediated by a specific form of trivalent arsenic, As 2 O 3 , highly effective for the treatment of hematological malignancies [62,63] as well as other types of tumors [64][65][66].…”

Arsenic-Based Anticancer-Combined Therapy: Novel Mechanism Inducing Apoptosis of Cancer Cells

“…Guilbert et al reported that ATO suppresses rapamycin (specific mTOR inhibitor)-induced phosphorylation of both ERK and Akt (Ser473), which leads to enhancement of the anticancer effect of rapamycin in vivo [24]. Cotylenin A (CN-A), a plant growth regulator, was reported to exert a favorable antitumor effect on breast cancer cells when it was co-incubated with ATO in vitro [25]. The combined CN-A-ATO treatment decreased survivin expression and increased caspase-7 expression by partly mediating ROS generation [25].…”

“…Cotylenin A (CN-A), a plant growth regulator, was reported to exert a favorable antitumor effect on breast cancer cells when it was co-incubated with ATO in vitro [25]. The combined CN-A-ATO treatment decreased survivin expression and increased caspase-7 expression by partly mediating ROS generation [25]. It has been reported that melatonin, a known natural antioxidant, enhances ATO-induced apoptosis by mediating ROS generation-induced MAPK activation including p38 and JNK in human breast cancer cell lines MDA-MB-231 and SK-BR-3 [26].…”