<p>Rhein shows potent efficacy against non-small-cell lung cancer through inhibiting the STAT3 pathway</p>

Abstract

Background: Non-small-cell lung cancer (NSCLC) comprises about 85% of all lung cancers and is usually diagnosed at an advanced stage with poor prognosis. The IL-6/STAT3 signaling pathway plays a pivotal role in NSCLC biology. Rhein is a lipophilic anthraquinone extensively found in medicinal herbs. Emerging evidence suggests that Rhein has significant antitumor effects, supporting the potential uses of Rhein as an antitumor agent. Methods: Cell viability and colony formation were performed to examine Rhein's potent antiproliferative effect in human NSCLC cell lines PC-9, H460 and A549. Flow cytometry-based assay was employed to study whether Rhein could affect cell apoptosis and cycle. The expression level of P-STAT3, apoptosis and cycle-related proteins Bcl-2, Bax, MDM2, CDC2, P53 and CyclinB1 were detected by Western blotting. The xenograft models were used to evaluate the in vivo effect of Rhein. Results: We found that Rhein could significantly reduce the viability and stimulate apoptosis in human NSCLC cells in a dose-dependent manner. Western blot analysis results suggested that the antitumor effect of Rhein might be mediated via STAT3 inhibition. Rhein upregulated the expression of the proapoptotic protein Bax and downregulated the expression of the antiapoptotic protein Bcl-2. In addition, Rhein induced the arrest of NSCLC cells in the G2/M phase of the cell cycle and dose dependently inhibited the expression of cycle-related proteins. The Rhein also inhibited tumor growth in H460 xenograft models. Conclusion: Rhein shows potent efficacy against NSCLC through inhibiting the STAT3 pathway. Our results also suggest that Rhein has a promising potential to be used as a novel antitumor agent for the treatment of NSCLC.

Therapeutic Emergence of Rhein as a Potential Anticancer Drug: A Review of Its Molecular Targets and Anticancer Properties

“…In vitro Caco-2 p-ERK1/2↑ (at higher concentrations of rhein) [150] In vitro HT29, HCT116, Colo205, SW620 HIF-1α↓, PD-L1↓, VEGF↓, COX-2↓, galectin-1↓ [98] In vitro HCT116, SW620 p-STAT3↓ [151] Glioma In vitro F98 ERK1/2↓ [152] In vitro T98G, U87, U251 Ac-K100↑, NDRG1↑ [153] Leukemia In vivo EU-1 injected SCID mice MDM2↓, p53↑ [154] In vitro HL-60 Cleaved caspase↑, cleaved PARP↑, cleaved Bid↑, ∆Ψm↓ [145] In vitro NB4 p-ERK↑, Caspase-3↑ [155] Liver cancer In vitro and in vivo HepG2, HepG2 injected BALB/c-nu mice β-catenin↓, S phase arrest↑ [111] In vitro HepG2 CD95↑, p53↑, p21/WAF↑, mCD95L↑, sCD95L↑ [96] In vitro BEL-7402 c-Myc↓, Caspase-3↑, S phase arrest↑ [54] In vitro SMMC-7721, SMMC-7721/DOX ATP synthesis↓, inner ∆Ψm↓ [156] In vitro HepG2, Huh7 ROS↑, p-c-Jun↑, Caspase-3↑ [55] Lung cancer In vitro and in vivo PC-9, H460, A549, H460 xenograft mice STAT3↓, Bax↑, Bcl-2↓, G2/M phase arrest↑ [157] In vitro A549 p-PI3K↓, Akt↓, mTOR↓, Bcl-2↓ [158] In vitro A549 G0/G1 phase arrest↑, GADD153↑, GRP78↑, Cyt c↑,…”

“…Some preclinical studies also showed the regulation of STAT3, Bax, and Bcl-2 expression pathway by rhein in A549 cells. It was shown that the treatment of rhein halted the cell cycle at G2/M phase via downregulation of cyclin B1, MDM2, and p-53 expression levels in H460 and PC-9 cells [157].…”

Natural compound rhein suppresses colorectal cancer cells growth through mTOR/p70S6 kinase pathway in vitro and in vivo

“…Rhein is a natural anthraquinone found in several medicinal plants [10], and it has been reported to possess a wide range of biological activities. Recent studies have demonstrated that rhein exhibited potent e cacy in inhibiting tumor growth [11,12,17,30]. However, the mechanisms underlying its anticancer effects of rhein remain poorly elucidated.…”

“…Rhein (4, 5-dihydroxyanthraquinone-2carboxylic acid) is a natural anthraquinone found in several medicinal plants, including Rheum palmatum, Polygonum multi orum, Aloe barbadensis, and Cassia tora [10]. A previous study suggested that rhein strongly inhibited non-small-cell lung cancer cells growth in vitro and in vivo by suppressing STAT3 pathway [11]. Rhein also induced HepaRG cell death via S phase cell cycle arrest and increased apoptosis [12].…”

Quinonoids: Therapeutic Potential for Lung Cancer Treatment

“…The STAT3 signal transduction pathway plays a key role in the biology of NSCLC. Yang et al [23] found that rhein, a lipophilic anthraquinone, might exert its antilung cancer effect by inhibition of STAT3. Rhein can markedly reduce viabilities and induce apoptosis in human lung cancer A549, PC9, and H460 cells.…”