Red ginseng has been used in traditional medicine for centuries in Asia. In this study, we evaluated four types of red ginseng grown in different areas (Chinese red ginseng, Korean red ginseng A, Korean red ginseng B, and Korean red ginseng C) for their ability to inhibit lung tumor formation and growth induced by the carcinogen benzo(a)pyrene (B(a)P) in A/J mice and found that Korean red ginseng B was the most effective at lowering the tumor load among the four red ginseng varieties. Moreover, we analyzed the levels of various ginsenosides (Rg1, Re, Rc, Rb2, Rb3, Rb1, Rh1, Rd, Rg3, Rh2, F1, Rk1, and Rg5) in four kinds of red ginseng extract and found that Korean red ginseng B had the highest level of ginsenoside Rg3 (G-Rg3), which suggested that G-Rg3 may play an important role in its therapeutic efficacy. This work revealed that the bioavailability of G-Rg3 was relatively poor. However, when G-Rg3 was coadministered with verapamil, a P-glycoprotein inhibitor, the G-Rg3 efflux in Caco-2 cells was lowered, the small intestinal absorption rate of G-Rg3 in the rat models was increased, the concentration levels of G-Rg3 were elevated in the intestine and plasma, and its tumor-preventive abilities in the tumorigenesis rat model induced by B(a)P were also augmented. We also found that G-Rg3 reduced B(a)P-induced cytotoxicity and DNA adduct formation in human lung cells and rescued phase II enzyme expression and activity through Nrf2 pathways, which may be the potential mechanisms underlying the inhibitory effects of G-Rg3 on lung tumorigenesis. Our study showed a potentially vital role of G-Rg3 in targeting lung tumors in murine models. The oral bioavailability of this ginsenoside was augmented by targeting P-glycoprotein, which allowed the molecule to exert its anticancer effects.

Backgrounds Lung cancer is one of the most frequently diagnosed cancers and the leading cause of cancer-related deaths worldwide. Deep understanding of chemoresistance will lead to remarkable progress in lung cancer treatment strategy. Cholesterol accumulation was associated with cisplatin resistance in lung cancer treatment. And we found the degree of cisplatin resistance was correlated with the expression of the cholesterol synthesis HMGCR. Methods We analyzed a group of 42 lung cancer patients who received cisplatin treatment after lung resection surgery. The expression of HMGCR and its correlation with cholesterol in lung cancer cell lines were determined by qRT-PCR and ELISA analyses. We focus on the function and mechanism of HMGCR in lung cancer and reveal that knockdown of HMGCR expression inhibits the proliferation, colony formation, and migration of lung cancer cell lines in vitro or in vivo and dramatically enhances the efficacy of cisplatin. Results Through mechanism studies, we illustrate that SIAH1, an E3 ubiquitin-protein ligase, ubiquitination modifies HMGCR and inhibits efflux protein activity via regulating cholesterol synthesis. In vivo experiments showed that SIAH1 overexpression or using HMGCR knockdown retard tumor growth and enhanced the efficacy of cisplatin. In summary, HMGCR affects cholesterol metabolism by regulating key enzymes in cholesterol synthesis, thereby reducing drug sensitivity. Conclusion This study indicates that lung cancer patients with lower HMGCR levels may lead to a better prognosis and provide a potential treatment by SIAH1 overexpression for lung cancer patients with cisplatin resistance.