Sanguinarine Induces Apoptosis Pathway in Multiple Myeloma Cell Lines via Inhibition of the JaK2/STAT3 Signaling

Abstract

Sanguinarine (SNG), a benzophenanthridine alkaloid, has displayed various anticancer abilities in several vivo and in vitro studies. However, the anticancer potential of SNG is yet to be established in multiple myeloma (MM), a mostly incurable malignancy of plasma cells. In this study, we aimed to investigate the potential anti-proliferative and pro-apoptotic activities of SNG in a panel of MM cell lines (U266, IM9, MM1S, and RPMI-8226). SNG treatment of MM cells resulted in a dose-dependent decrease in cell viability through mitochondrial membrane potential loss and activation of caspase 3, 9, and cleavage of PARP. Pre-treatment of MM cells with a universal caspase inhibitor, Z-VAD-FMK, prevented SNG mediated loss of cell viability, apoptosis, and caspase activation, confirming that SNG-mediated apoptosis is caspase-dependent. The SNG-mediated apoptosis appears to be resulted from suppression of the constitutively active STAT3 with a concomitant increase in expression of protein tyrosine phosphatase (SHP-1). SNG treatment of MM cells leads to down-regulation of the anti-apoptotic proteins including cyclin D, Bcl-2, Bclxl, and XIAP. In addition, it also upregulates pro-apoptotic protein, Bax. SNG mediated cellular DNA damage in MM cell lines by induction of oxidative stress through the generation of reactive oxygen species and depletion of glutathione. Finally, the subtoxic concentration of SNG enhanced the cytotoxic effects of anticancer drugs bortezomib (BTZ) by suppressing the viability of MM cells via induction of caspase-mediated apoptosis. Altogether our findings demonstrate that SNG induces mitochondrial and caspase-dependent apoptosis, generates oxidative stress, and suppresses MM cell lines proliferation. In addition, co-treatment of MM cell lines with sub-toxic doses of SNG and BTZ potentiated the cytotoxic activity. These results would suggest that SNG could be developed into therapeutic agent either alone or in combination with other anticancer drugs in MM.

Sanguinarine Induces Apoptosis in Papillary Thyroid Cancer Cells via Generation of Reactive Oxygen Species

“…STAT3-mediated signaling is often associated with aberrant proliferation and therapeutic resistance of thyroid cancer cells [10,53,54]. Furthermore, STAT3 has been shown to be a major signaling molecule associated with human carcinogenesis, which also causes resistance to cancer therapy and induces stemness [55][56][57][58]; hence, the potential of SNG to suppress the activated STAT3 activity in PTC cells supports its anticancer potential, which is in agreement with previous findings [19,26]. Apoptosis, or programmed cell death, is a vital biological phenomenon essential for homeostasis; it is regulated by a number of signaling proteins, and once deregulated, it leads to the development of various pathological conditions including cancer and therapeutic resistance [59].…”

“…The role of STAT3 in thyroid malignancies is relatively less studied, however, there are data from some in vitro as well as in vivo studies [12][13][14][15], including the recent investigations on how STAT3 plays a critical role in noncoding RNA-mediated alterations related to the thyroid cancer pathogenesis [16][17][18]. In addition, the critical role of STAT3 in the development of both solid and hematological human malignancies has been reported by many research groups [19][20][21]. STAT3 is, therefore, a legitimate target for cancer management and therapy [20,22].…”

“…In the current study, we evaluated the effect of a natural compound, SNG (Figure 1), as an anticancer agent against PTC cells. SNG is generally obtained from the roots of Sanguinaria canadensis and chemically categorized as benzophenanthridine alkaloid [19,24]. In plants, biosynthesis of SNG involves the combination of 4-hydroxyphenyl-acetaldehyde and dopamine to form norcoclaurine; this is followed by the addition of methyl hydroxyl groups.…”

“…The final step in the synthesis of SNG involves the conversion of precursor dihydrosanguinarine to SNG by the enzyme dihydrobenzophenanthridine oxidase. A number of studies have shown the therapeutic potential of SNG over a range of human pathological and toxicological conditions including cancer; for example, lung cancer [25], cervical cancer [26], gastric cancer [27,28], liver cancer [29,30], multiple myeloma [19], acute lymphoblastic leukemia [31], prostate cancer [32], colorectal cancer [33], ovary cancer [34] and pancreatic cancer [35]. Recently Achkar et al [36] extensively reviewed the anticancer features of SNG and, additionally, antioxidant/anti-inflammatory [37][38][39], antifungal [40,41], antibacterial [42,43], anthelmintic [44] and other pharmacological activities of SNG have also been reported.…”

Two Natural Alkaloids Synergistically Induce Apoptosis in Breast Cancer Cells by Inhibiting STAT3 Activation

“…STAT3 signaling pathway plays a crucial role in proliferation (Bcl-2, Survivin), angiogenesis (HIF1α, VEGF), and epithelial-mesenchymal transition (Vimentin, MMP-9) in breast cancer cells and has been validated as a drug target for cancer therapy [41][42][43]. Several agents have been proved to induce apoptosis by inhibiting the STAT3 pathway, such as chelerythrine, sanguinarine and 4-chlorobenzoyl berbamine [44][45][46]. PL was identified as a direct STAT3 inhibitor with potent activity against breast cancer [47], while the role of PP to STAT3 regulation in breast cancer has not yet been reported.…”