Thymoquinone upregulates miR‐125a‐5p, attenuates STAT3 activation, and potentiates doxorubicin antitumor activity in murine solid Ehrlich carcinoma

Abstract

In breast cancer, there has been evidence of atypical activation of signal transduction and activators of transcription 3 (STAT3). Thymoquinone (TQ) exerts its antineoplastic effect through diverse mechanisms, including STAT3 inhibition. The tumor suppressor, microRNA-125a-5p was reported to be downregulated in various breast cancer cells. Therefore, we investigated the influence of TQ and/or doxorubicin on microRNA-125a-5p and its correlation with STAT3 activation as well as tumor growth in mice bearing solid Ehrlich tumors. We found that TQ markedly suppressed inducible and constitutive phosphorylation of STAT3 in tumor tissue without affecting STAT5. Moreover, it attenuated tumor growth, downregulated STAT3 downstream target proteins, and increased the apoptotic activities of caspase-3 and -9. Interestingly, TQ-elicited synergism of doxorubicin anti-neoplastic activity was coupled with upregulation of tumoral microRNA-125a-5p. Taken together, the current findings raise the potential of TQ as a promising chemomodulatory adjuvant to augment mammary carcinoma sensitivity to doxorubicin.

Modulation of AKT Pathway-Targeting miRNAs for Cancer Cell Treatment with Natural Products

“…Thymoquinone, the main bioactive compound derived from Nigella sativa , inhibits the migration of breast cancer cells by upregulating miR-34a-5p [ 182 ]. Thymoquinone induces apoptosis by downregulating the activation (phosphorylation) of STAT3 [ 196 ]. Moreover, thymoquinone has chemosensitization effects.…”

“…Moreover, thymoquinone has chemosensitization effects. The combined treatment including thymoquinone and doxorubicin shows synergistic antiproliferative effects against murine solid Ehrlich carcinoma through the upregulation of miR-125a-5p [ 196 ]. Phytic acid, a plant seed-derived natural product, improved the apoptotic effects of oxaliplatin in a 1,2-dimethylhydrazine-induced colorectal cancer model by downregulating miR-224-5p (miR-224) and miR-200a-3p (miR-200a) [ 183 ] ( Table 3 ).…”

miRNAs as short non-coding RNAs in regulating doxorubicin resistance

“…Curcumol promotes expression level of miRNA‐181b‐2‐3p to down‐regulate ABCC3, leading to DOX sensitivity of breast tumor cells in vitro and in vivo (Zeng et al 2020). Thympquinone is another natural product employed in mediating DOX sensitivity of tumor cells (Atteia et al 2021). Increasing evidence has revealed role of STAT3 signaling in increasing progression of tumor cells and inducing drug resistance.…”

“…Increasing evidence has revealed role of STAT3 signaling in increasing progression of tumor cells and inducing drug resistance. As anti‐cancer agent, thymoquinone is able to increase expression level of miRNA‐125a‐5p to suppress STAT3 signaling, resulting in DOX sensitivity of cancer cells (Atteia et al 2021). Taking everything together, these studies highlight the fact that anti‐tumor agents are able to regulate miRNAs in increasing DOX sensitivity of tumor cells (Hsieh et al 2020; Gao et al 2017; Gao et al 2018).…”

Plants as a Source of Anticancer Agents: From Bench to Bedside

“…Along with TQ’s impairment of autophagic flux and inhibition of the EMT and cell invasion via activation of the miR-877-5p/PD-L1 (programmed death ligand 1) axis in bladder carcinoma cells and the expression of Beclin-1 and LC3 in triple-negative breast cancer (TNBC) cells, it suppresses the pathways related to cell migration/invasion and angiogenesis, including Integrin-β1, VEGF, MMP-2, and MMP-9 [ 248 , 249 ]. Thymoquinone upregulates miR-125a-5p, attenuates STAT3 activation, and potentiates doxorubicin antitumor activity in murine solid Ehrlich carcinoma [ 250 ].…”