Shikonin is a novel and selective IMPDH2 inhibitor that target triple‐negative breast cancer

Abstract

Triple‐negative breast cancer (TNBC) is heterogeneous disease with a poor prognosis. It is therefore important to explore novel therapeutic agents to improve the clinical efficacy for TNBC. The inosine 5′‐monophosphate dehydrogenase 2 (IMPDH2) is a rate‐limiting enzyme in the de novo synthesis of guanine nucleotides. It is always overexpressed in many types of tumors, including TNBC and regarded as a potential target for cancer therapy. Through screening a library of natural products, we identified shikonin, a natural bioactive component of Lithospermum erythrorhizon, is a novel and selective IMPDH2 inhibitor. Enzymatic analysis using Lineweaver–Burk plot indicates that shikonin is a competitive inhibitor of IMPDH2. The interaction between shikonin and IMDPH2 was further investigated by thermal shift assay, fluorescence quenching, and molecular docking simulation. Shikonin treatment effectively inhibits the growth of human TNBC cell line MDA‐MB‐231, and murine TNBC cell line, 4T1 in a dose‐dependent manner, which is impaired by exogenous supplementation of guanosine, a salvage pathway of purine nucleotides. Most importantly, IMPDH2 knockdown significantly reduced cell proliferation and conferred resistance to shikonin in TNBC. Collectively, our findings showed the natural product shikonin as a selective inhibitor of IMPDH2 with anti‐TNBC activity, impelling its further study in clinical trials.

Shikonin inhibits the Warburg effect, cell proliferation, invasion and migration by downregulating PFKFB2 expression in lung cancer

“…Guo et al ( 37 ) also found that shikonin inhibited cell proliferation and induced apoptosis in glioma. Wang et al ( 38 ) reported that shikonin inhibited the proliferation and promoted apoptosis of breast cancer cells. The results of the present study demonstrated that shikonin could inhibit proliferation, migration and invasion, and increase the apoptosis of A549 cells in a dose-dependent manner, which were consistent with the findings of previous studies ( 36 – 38 ).…”

“…Wang et al (38) reported that shikonin inhibited the proliferation and promoted apoptosis of breast cancer cells. The results of the present study demonstrated that shikonin could inhibit proliferation, migration and invasion, and increase the apoptosis of A549 cells in a dose-dependent manner, which were consistent with the findings of previous studies (36)(37)(38). However, the results of the present study showed a lower apoptosis rate, which is different to the results obtained in the aforementioned studies.…”

The anti-tumor effects of the combination of microwave hyperthermia and lobaplatin against breast cancer cells in vitro and in vivo

“…MDA-MB-231 and 4T1 were selected, for further investigation since they are highly invasive TNBC breast cancer cell lines [18], [19]. The 4T1 tumor is highly tumorigenic; unlike most tumor models, it can spontaneously metastasize from the primary tumor in the mammary gland to multiple distant sites [20].…”

The Natural Products and Extracts: Anti‐Triple‐Negative Breast Cancer in Vitro

“…It observably inhibited cell viabilities of MDA‐MB‐231 and 4T1 in a dose‐dependent manner with IC 50 of 2.08 and 1.45 μM, respectively. It stabilized IMPDH2 in MDA‐MB‐231 and 4T1 cells in cellular thermal shift assay (CETSA), illustrating that shikonin inhibited IMPDH2 directly in TNBC cells [55] …”

“…It stabilized IMPDH2 in MDA-MB-231 and 4T1 cells in cellular thermal shift assay (CETSA), illustrating that shikonin inhibited IMPDH2 directly in TNBC cells. [55] OHPer-MAng (25) (Figure 8) was isolated from the roots of the vegetable specimen A.cordata obtained (Dec. In the docking models, OHPer-MAng establishes great non-bonding interactions with the lateral chains of Tyr235, Hys201, Tyr246, Ser203, Asn207, and Gly233 located at the catalytic site of PARP-1.…”