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Ovatodiolide targets chronic myeloid leukemia stem cells by epigenetically upregulating hsa-miR-155, suppressing the BCR-ABL fusion gene and dysregulating the PI3K/AKT/mTOR pathway.

ABSTRACT: Chronic myeloid leukemia (CML) is a myeloproliferative pathology, originating from the hematopoietic cancer stem cells (hCSCs) due to the Bcl-Abl Philadelphia chromosome transformation. However, targeting these hCSCs as an effective anti-CML strategy is relatively less explored. Ovatodiolide (Ova) is a natural diterpenoid isolate of Anisomeles indica with broad anticancer activity. In this study, we investigated the anti-hCSCs potential of Ova against CD34+/CD38-, CD34+/CD38+, and unsorted K562 cell lines using flow cytometry, western blot, RT-PCR, genomic mapping, and tumorsphere formation assays. We demonstrated that compared to unsorted K562 and CD34+/CD38+, CD34+/CD38- cells were significantly enriched with Oct4, Sox2, CD133, Bcr-Abl, p-CrkL and p-Stat5 protein and/or mRNA. Furthermore, we showed that Ova alone or by enhancing the therapeutic potential of Imatinib, reduced the viability of CML cell lines, dose-dependently, irrespective of the cancer stemness, as well as markedly inhibit the Bcr-Abl, p-CrkL, Stat5, and MDR protein expression levels in CD34+ cells. Mechanistic investigations revealed a significant up-regulation of hsa-miR-155, which resulted in the reduction of dysregulating the PIK3CA expression in Ova-treated K562 CD34+/CD38- cells. Additionally, Ova alone or in combination with Imatinib suppressed the hCSC traits of the CD34+/CD38- cells, resulting in loss of their ability to form tumorspheres, enhanced apoptosis, increase in the Bax/Bcl-2 ratio, and dysregulation of the PI3K/AKT/mTOR signaling pathway. Together, these results demonstrate the PI3K/AKT/mTOR signaling-mediated anti-hCSC effect of Ova in CML, as well as suggest a likely role for Ova as a small molecule PI3K/mTOR dual inhibitor, thus, extending its potential benefit to other mTOR-mediated pathologies.

SUBMITTER: Tu YX

PROVIDER: S-EPMC5790462 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Ovatodiolide targets chronic myeloid leukemia stem cells by epigenetically upregulating hsa-miR-155, suppressing the BCR-ABL fusion gene and dysregulating the PI3K/AKT/mTOR pathway.

Tu Yue-Xing YX Wang Shi-Bing SB Fu Luo-Qin LQ Li Shuang-Shuang SS Guo Qian-Peng QP Wu Yi Y Mou Xiao-Zhou XZ Tong Xiang-Min XM

Oncotarget 20171214 3

Chronic myeloid leukemia (CML) is a myeloproliferative pathology, originating from the hematopoietic cancer stem cells (hCSCs) due to the Bcl-Abl Philadelphia chromosome transformation. However, targeting these hCSCs as an effective anti-CML strategy is relatively less explored. Ovatodiolide (Ova) is a natural diterpenoid isolate of Anisomeles indica with broad anticancer activity. In this study, we investigated the anti-hCSCs potential of Ova against CD34+/CD38-, CD ...[more]

PMID: 29423045

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Project description:Background:Imatinib and second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib have statistically significantly improved the life expectancy of chronic myeloid leukemia (CML) patients; however, resistance to TKIs remains a major clinical challenge. Although ponatinib, a third-generation TKI, improves outcomes for patients with BCR-ABL-dependent mechanisms of resistance, including the T315I mutation, a proportion of patients may have or develop BCR-ABL-independent resistance and fail ponatinib treatment. By modeling ponatinib resistance and testing samples from these CML patients, it is hoped that an alternative drug target can be identified and inhibited with a novel compound. Methods:Two CML cell lines with acquired BCR-ABL-independent resistance were generated following culture in ponatinib. RNA sequencing and gene ontology (GO) enrichment were used to detect aberrant transcriptional response in ponatinib-resistant cells. A validated oncogene drug library was used to identify US Food and Drug Administration-approved drugs with activity against TKI-resistant cells. Validation was performed using bone marrow (BM)-derived cells from TKI-resistant patients (n?=?4) and a human xenograft mouse model (n?=?4-6 mice per group). All statistical tests were two-sided. Results:We show that ponatinib-resistant CML cells can acquire BCR-ABL-independent resistance mediated through alternative activation of mTOR. Following transcriptomic analysis and drug screening, we highlight mTOR inhibition as an alternative therapeutic approach in TKI-resistant CML cells. Additionally, we show that catalytic mTOR inhibitors induce autophagy and demonstrate that genetic or pharmacological inhibition of autophagy sensitizes ponatinib-resistant CML cells to death induced by mTOR inhibition in vitro (% number of colonies of control[SD], NVP-BEZ235 vs NVP-BEZ235+HCQ: 45.0[17.9]% vs 24.0[8.4]%, P = .002) and in vivo (median survival of NVP-BEZ235- vs NVP-BEZ235+HCQ-treated mice: 38.5 days vs 47.0 days, P = .04). Conclusion:Combined mTOR and autophagy inhibition may provide an attractive approach to target BCR-ABL-independent mechanism of resistance.

Dataset Information

Ovatodiolide targets chronic myeloid leukemia stem cells by epigenetically upregulating hsa-miR-155, suppressing the BCR-ABL fusion gene and dysregulating the PI3K/AKT/mTOR pathway.

Publications

Ovatodiolide targets chronic myeloid leukemia stem cells by epigenetically upregulating hsa-miR-155, suppressing the BCR-ABL fusion gene and dysregulating the PI3K/AKT/mTOR pathway.

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