| Description: |
Shikonin(Shikonine), a potent and specific Pyruvate kinase M2 (PKM2) inhibitor, has antibacterial, antitumor, and anti-inflammatory effects, it provides neuroprotection by reducing the release of various proinflammatory molecules from activated microglia. Shikonin can inhibit VEGF-induced angiogenesis and suppress tumor growth in lewis lung carcinoma-bearing mice. |
| Targets: |
Antifection | VEGFR | PKM2 | Cdk4 | HIV | CXCR4 |
| In vitro: |
| Oncogene, 2011, 30(42):4297-306. | | Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2.[Pubmed: 21516121] | We recently reported that shikonin(Shikonine) and its analogs were a class of necroptotic inducers that could bypass cancer drug resistance. However, the molecular targets of shikonin are not known.
METHODS AND RESULTS:
Here, we showed that shikonin and its analogs are inhibitors of tumor-specific pyruvate kinase-M2 (PKM2), among which shikonin and its enantiomeric isomer alkannin were the most potent and showed promising selectivity, that is, shikonin and alkannin at concentrations that resulted in over 50% inhibition of PKM2 activity did not inhibit PKM1 and pyruvate kinase-L (PKL). Shikonin and alkannin significantly inhibited the glycolytic rate, as manifested by cellular lactate production and glucose consumption in drug-sensitive and resistant cancer cell lines (MCF-7, MCF-7/Adr, MCF-7/Bcl-2, MCF-7/Bcl-x(L) and A549) that primarily express PKM2. HeLa cells transfected with PKM1 showed reduced sensitivity to shikonin- or alkannin-induced cell death. To the best of our knowledge, shikonin and alkannin are the most potent and specific inhibitors to PKM2 reported so far.
CONCLUSIONS:
As PKM2 universally expresses in cancer cells and dictates the last rate-limiting step of glycolysis vital for cancer cell proliferation and survival, enantiomeric shikonin and alkannin may have potential in future clinical application. | | Front Pharmacol. 2016 Aug 23;7:270. | | Shikonin Inhibits Intestinal Calcium-Activated Chloride Channels and Prevents Rotaviral Diarrhea.[Pubmed: 27601995 ] | Secretory diarrhea remains a global health burden and causes major mortality in children. There have been some focuses on antidiarrheal therapies that may reduce fluid losses and intestinal motility in diarrheal diseases.
METHODS AND RESULTS:
In the present study, we identified shikonin(Shikonine) as an inhibitor of TMEM16A chloride channel activity using cell-based fluorescent-quenching assay. The IC50 value of shikonin was 6.5 μM. Short-circuit current measurements demonstrated that shikonin inhibited Eact-induced Cl(-) current in a dose-dependent manner, with IC50 value of 1.5 μM. Short-circuit current measurement showed that shikonin exhibited inhibitory effect against CCh-induced Cl(-) currents in mouse colonic epithelia but did not affect cytoplasmic Ca(2+) concentration as well as the other major enterocyte chloride channel conductance regulator. Characterization study found that shikonin inhibited basolateral K(+) channel activity without affecting Na(+)/K(+)-ATPase activities. In vivo studies revealed that shikonin significantly delayed intestinal motility in mice and reduced stool water content in a neonatal mice model of rotaviral diarrhea without affecting the viral infection process in vivo.
CONCLUSIONS:
Taken together, the results suggested that shikonin inhibited enterocyte calcium-activated chloride channels, the inhibitory effect was partially through inhbition of basolateral K(+) channel activity, and shikonin could be a lead compound in the treatment of rotaviral secretory diarrhea. |
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| In vivo: |
| PLoS One. 2015 May 11;10(5):e0126459. | | Shikonin Suppresses Skin Carcinogenesis via Inhibiting Cell Proliferation.[Pubmed: 25961580 ] | The M2 isoform of pyruvate kinase M2 (PKM2) has been shown to be up-regulated in human skin cancers.
METHODS AND RESULTS:
To test whether PKM2 may be a target for chemoprevention, shikonin(Shikonine), a natural product from the root of Lithospermum erythrorhizon and a specific inhibitor of PKM2, was used in a chemically-induced mouse skin carcinogenesis study. The results revealed that shikonin treatment suppressed skin tumor formation. Morphological examinations and immunohistochemical staining of the skin epidermal tissues suggested that shikonin inhibited cell proliferation without inducing apoptosis. Although shikonin alone suppressed PKM2 activity, it did not suppress tumor promoter-induced PKM2 activation in the skin epidermal tissues at the end of the skin carcinogenesis study. To reveal the potential chemopreventive mechanism of shikonin, an antibody microarray analysis was performed, and the results showed that the transcription factor ATF2 and its downstream target Cdk4 were up-regulated by chemical carcinogen treatment; whereas these up-regulations were suppressed by shikonin. In a promotable skin cell model, the nuclear levels of ATF2 were increased during tumor promotion, whereas this increase was inhibited by shikonin. Furthermore, knockdown of ATF2 decreased the expression levels of Cdk4 and Fra-1 (a key subunit of the activator protein 1.
CONCLUSIONS:
In summary, these results suggest that shikonin, rather than inhibiting PKM2 in vivo, suppresses the ATF2 pathway in skin carcinogenesis. |
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