Artemisinin-Daumone Hybrid Inhibits Cancer Cell-Mediated Osteolysis by Targeting Cancer Cells and Osteoclasts

Abstract

Background/Aims: Bone metastasis of cancer cells decreases patient survival and quality of life. Hybridization via the covalent coupling of two bioactive natural products is a useful strategy for developing more potent anticancer agents by enhancing their bioavailability and avoiding drug resistance. Methods: The in vivo activities of artemisinin-daumone hybrid 15 (ARTD) were estimated in cancer cell-inoculated mice and ovariectomized mice. The viability, migration, and invasion of cancer cells were measured via MTT, wound-healing, and transwell invasion assays. ARTD-regulated transcription factors were detected with an RT² profiler PCR array kit and Western blotting. Osteoclastogenesis and osteoclast activity were detected with tartrate-resistant acid phosphatase staining, a pit formation assay, gelatin zymography, and a cathepsin K ELISA assay. Results: ARTD blocked cancer-associated osteolysis more potently than artemisinin in mice with intratibially inoculated breast cancer or lung cancer cells. ARTD inhibited the viability, migration, and invasion of breast and lung cancer cells in the absence or presence of transforming growth factor-β1. ARTD treatment induced the expression of tumor suppressive activating transcription factor 3 and inhibited oncogenic E2F transcription factor 1 expression at the mRNA and protein levels. ARTD inhibited receptor activator of nuclear factor kappa-B ligand-induced osteoclast formation and bone resorbing activity by reducing the secreted levels of matrix metalloproteinase-9 and cathepsin K. Furthermore, ARTD prevented estrogen deficiency-induced bone loss in ovariectomized mice. Conclusion: ARTD may be a promising candidate for inhibiting cancer-induced bone destruction. The application of ARTD may be extended to patients with chemotherapy-induced ovarian failure or postmenopausal osteoporosis.

Artemisinins as Anticancer Drugs: Novel Therapeutic Approaches, Molecular Mechanisms, and Clinical Trials

“…This transcript factor has been confirmed to be strongly associated with aggressiveness and resistance to cancer therapies (Zhang et al, 2020). Ma et al found that ARTdaumone hybrids inhibited cancer cell-mediated osteolysis by upregulating the level of activating transcription factor 3 and downregulating the level of E2F transcription factor 1 and hepatocyte nuclear factor 4 alpha (Ma et al, 2018). Li et al found that ART-chemotherapeutic conjugates inhibited the growth and proliferation of ovarian cancer cells, resulting in S-phase arrest, apoptosis and epithelial mesenchymal transition (EMT) (Li et al, 2016).…”

“…This approach is often used in searching for safe, effective and specific innovative medicines for cancer therapy (Letis et al, 2017;Yu et al, 2018;Zborovskii et al, 2018). Many studies of ARTs have generated new hybrids, such as ART-derivative-N-heterocyclic carbene (NHC)-gold(I)hybrids (Zhang et al, 2020), ART-daumone hybrids (Ma et al, 2018), DHA-bile acid hybrids (Letis et al, 2017;Marchesi et al, 2019), DHA-cinnamic acid hybrids (Xu et al, 2016), DHAcoumarin hybrids (Yu et al, 2018) and ART-chemotherapeutic agent conjugates (Li et al, 2016), et al, with more potent activity than with either agent alone ( Table 1). We designed and synthesized DHA-cinnamic acid ester derivatives modified at two positions, C-9 and C-12.…”

“…New partner drugs of ARTs have been suggested to establish combination-treatment regimen for antimalaria to reduce resistance risk . Successful combinations of Inhibit Nrf2 transcriptional activity (Zhang et al, 2020) ART-daumone hybrids MDA-MB-231, A549 Tumor suppressive activating transcription factor 3↑, oncogenic E2F transcription factor 1↓, inhibit osteoclast formation, MMP 9↓, cathepsin K↓ (Ma et al, 2018) DHA-bile acid hybrids HL-60, HepG2, Induce apoptosis (Marchesi et al, 2019) CCRF-CEM, CEM/ADR5000 Enhance cytotoxicity, low cross resistance (Letis et al, 2017) DHA-cinnamic acid hybrids…”

TRICHOME AND ARTEMISININ REGULATOR 2 positively regulates trichome development and artemisinin biosynthesis in Artemisia annua

“…Artemisinin, a kind of sesquiterpene lactone endoperoxide, is extracted from tranditional Chinese herb Artemisia annua . Nowadays, new artemisinin‐based treatments are applied in the treatment of other diseases, and a substantial amount of artemisinin is required to meet the clinical treatment (Wu et al ., 2016; Kayentao et al ., 2018; Ma et al ., 2018). Although artemisinin and its precursor artemisinic acid have been synthesized in several species, like yeast, Escherichia coli , Nicotiana benthamiana , and Physcomitrella patens , plant‐derived artemisinin is still an essential and economical choice due to the limited production from synthetic methods (Martin et al ., 2003; Paddon et al ., 2013; Wang et al ., 2016; Khairul et al ., 2017).…”

<p>Exploration of the Potential Biomarkers of Papillary Thyroid Cancer (PTC) Based on RT² Profiler PCR Arrays and Bioinformatics Analysis</p>

“…For example, RT Profiler PCR array has been used by many scholars to explore the diagnostic targets of other tumors in recent years, and a lot of achievements have been made. [12][13][14] Bioinformatics is a new discipline emerging with the launch of the human genome project, 15 and has established a fundamental position in the life sciences. Mining and analyzing the massive data based bioinformatics also allow us to screen key genes or pathways associated with the diseases.…”