Because of the essential role of signal transducer and activator of transcription 3 (STAT3) in proliferation, anti-apoptosis, and chemoresistance of multiple myeloma (MM), we investigated whether icariin, a prenylated flavonol glycoside, inhibits both constitutive and inducible STAT3 activation in human myeloma cell lines. We noted that icariin could block constitutive STAT3 phosphorylation as well as its nuclear translocation and DNA binding ability in U266 cells. Icariin also suppressed IL-6-induced STAT3 activation through the inhibition of upstream kinases (Janus activated kinase-1 and -2, and c-Src). We found that icariin downregulated the protein expression of STAT3 downstream target gene products such as Bcl-2, Bcl-xl, survivin, IAP-1/2, COX-2, VEGF, and matrix metallopeptidase 9 (MMP-9) in a concentration-dependent manner. Moreover, this flavonoid also exhibited the capacity to significantly induce apoptosis and suppress proliferation of MM cells. Interestingly, this agent also significantly potentiated the apoptotic effects of bortezomib through the suppression of STAT3 activation in MM cells. Altogether, our data indicates that the potential application of icariin as a STAT3 blocker in myeloma therapy.
Oxymatrine (OMT) is a major alkaloid found in radix Sophorae flavescentis extract and has been reported to exhibit various pharmacological activities. We elucidated the detailed molecular mechanism(s) underlying the therapeutic actions of OMT in non-small cell lung cancer (NSCLC) cells and a xenograft mouse model. Because the STAT5 signaling cascade has a significant role in regulating cell proliferation and survival in tumor cells, we hypothesized that OMT may disrupt this signaling cascade to exert its anticancer effects. We found that OMT can inhibit the constitutive activation of STAT5 by suppressing the activation of JAK1/2 and c-Src, nuclear localization, as well as STAT5 binding to DNA in A549 cells and abrogated IL-6-induced STAT5 phosphorylation in H1299 cells. We also report that a sub-optimal concentration of OMT when used in combination with a low dose of paclitaxel produced significant anti-cancer effects by inhibiting cell proliferation and causing substantial apoptosis. In a preclinical lung cancer mouse model, OMT when used in combination with paclitaxel produced a significant reduction in tumor volume. These results suggest that OMT in combination with paclitaxel can cause an attenuation of lung cancer growth both in vitro and in vivo.
Farnesol, an acyclic sesquiterpene alcohol, is predominantly found in essential oils of various plants in nature. It has been reported to exhibit anti-cancer and anti-inflammatory effects, and also alleviate allergic asthma, gliosis, and edema. In numerous tumor cell lines, farnesol can modulate various tumorigenic proteins and/or modulates diverse signal transduction cascades. It can also induce apoptosis and downregulate cell proliferation, angiogenesis, and cell survival. To exert its anti-inflammatory/anti-oncogenic effects, farnesol can modulate Ras protein and nuclear factor kappa-light-chain-enhancer of activated B cells activation to downregulate the expression of various inflammatory mediators such as cyclooxygenase-2, inducible nitric oxide synthase, tumor necrosis factor alpha, and interleukin-6. In this review, we describe the potential mechanisms of action underlying the therapeutic effects of farnesol against cancers and inflammatory disorders. Furthermore, these findings support the clinical development of farnesol as a potential pharmacological agent in clinical studies.
Hypercholesterolemia has been found to be closely linked with a significant increase in both cancer incidence and mortality. However, the exact correlation between serum cholesterol levels and cancer has not been completely deciphered. Here we analyzed the effect of low‐density lipoprotein (LDL) cholesterol on prostate and pancreatic cancer cells. We noted that LDL induced a substantial STAT3 activation and JAK1, JAK2, Src activation in diverse prostate and pancreatic tumor cells. Moreover, LDL promoted cancer cell proliferation, migration, and invasion as well as upregulated the expression of diverse oncogenic gene products. However, deletion of LDL‐activated STAT3 in LNCaP and PANC‐1 cells and reduced LDL‐induced cell viability. Simvastatin (SV) treatment also alleviated LDL‐induced cell viability and migration ability in both the prostate and pancreatic tumor cells. These results demonstrate that LDL‐induced STAT3 activation may exert a profound effect on the proliferation and survival of tumor cells.
Casticin (CTC), one of the major components of Vitex rotundifolia L., has been reported to exert significant beneficial pharmacological activities and can function as an antiprolactin, anticancer, anti-inflammatory, neuroprotective, analgesic, and immunomodulatory agent. This study aimed at investigating whether the proapoptotic effects of CTC may be mediated through the abrogation of signal transducers and activators of transcription-3 (STAT3) signaling pathway in a variety of human tumor cells. We found that CTC significantly decreased cell viability in a concentration-dependent manner and suppressed cell proliferation in 786-O, YD-8, and HN-9 cells.CTC also induced programmed cell death that was found to be mediated via caspase-3 activation and induction of poly(ADP-ribose) polymerase cleavage. Interestingly, CTC repressed both constitutive and interleukin-6induced STAT3 activation in 786-O and YD-8 cells but only affected constitutive STAT3 phosphorylation in HN-9 cells. Moreover, CTC could potentiate ionizing radiation-induced apoptotic effects leading to the downregulation of STAT3 activation and thus may be used in combination with radiation against diverse malignancies. K E Y W O R D S apoptosis, cancer, casticin, radiation, signal transducers and activators of transcription-3 J Cell Biochem. 2019;120:9787-9798.wileyonlinelibrary.com/journal/jcb
Fangchinoline (FCN) derived from Stephaniae tetrandrine S. Moore can be employed to treat fever, inflammation, rheumatism arthralgia, edema, dysuria, athlete’s foot, and swollen wet sores. FCN can exhibit a plethora of anti-neoplastic effects although its precise mode of action still remains to be deciphered. Nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) can closely regulate carcinogenesis and thus we analyzed the possible action of FCN may have on these two signaling cascades in tumor cells. The effect of FCN on NF-κB and AP-1 signaling cascades and its downstream functions was deciphered using diverse assays in both human chronic myeloid leukemia (KBM5) and multiple myeloma (U266). FCN attenuated growth of both leukemic and multiple myeloma cells and repressed NF-κB, and AP-1 activation through diverse mechanisms, including attenuation of phosphorylation of IκB kinase (IKK) and p65. Furthermore, FCN could also cause significant enhancement in TNFα-driven apoptosis as studied by various molecular techniques. Thus, FCN may exhibit potent anti-neoplastic effects by affecting diverse oncogenic pathways and may be employed as pro-apoptotic agent against various malignancies.
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