Enhancement of the effects of gemcitabine against pancreatic cancer by oridonin via the mitochondrial caspase-dependent signaling pathway

Abstract

Gemcitabine is a first‑line chemotherapeutic agent used in the treatment of pancreatic cancer; however resistance of the disease to the drug often develops over time. Agents that can either enhance the effects of gemcitabine, or help to overcome the chemoresistance to the drug are needed for the successful treatment of pancreatic cancer. Oridonin is one such agent which is safe and multi‑targeted and has previously been shown to induce apoptosis in other tumor cells, through mitochondrial signaling pathways. The aims of the present study were to evaluate whether oridonin may enhance the effects of gemcitabine on pancreatic cancer in vitro and to investigate the possible mechanisms of this enhancement. In vitro studies have previously shown that oridonin can inhibit the proliferation of the Panc‑1 pancreatic cancer cell line, and potentiate gemcitabine‑induced apoptosis, which was shown to be associated with cell cycle arrest in the G1 phase. Western blot and quantitative polymerase chain reaction analyses demonstrated that the expression levels of the anti‑apoptotic gene Bcl‑2 and the Bcl‑2/Bax ratio in the oridonin and the oridonin plus gemcitabine groups were significantly downregulated as compared with the gemcitabine treatment and control groups. The expression levels of pro‑apoptotic genes Bax, cytochrome c (cyt c), and caspase‑3 and ‑9 in the oridonin and the combination groups were significantly upregulated as compared with the other two groups. The results suggested that oridonin improved the anti‑tumor effects of gemcitabine through the enhancement of gemcitabine‑induced apoptosis.This mechanism may be through the downregulation of Bcl‑2 expression and the upregulation of Bax expression, resulting in the reduction of the Bcl‑2/Bax ratio. These effects may promote the release of cyt c from the mitochondria into the cytoplasm thus triggering the mitochondrial apoptosis signaling pathway. Furthermore, caspase‑3 and ‑9 were shown to be activated as a result of the induction of apoptosis.

Oridonin upregulates PTEN through activating p38 MAPK and inhibits proliferation in human colon cancer cells

“…ORI has been used as a drug for antitumor, anti-microbial, anti-inflammatory and antioxidant for many years (18). It has been reported that ORI can inhibit proliferation and induce apoptosis in various cancer cells, such as breast, pancreatic, lung, gastric and prostate cancer (8,(19)(20)(21)(22)(23), as well as induce apoptosis and senescence in colon cancer cells (12,24). Our data also confirmed that ORI can inhibit proliferation and induce apoptosis in HCT116 cells concentration-dependently, as well as inhibit the tumor growth of colon cancer.…”

Apoptotic Pathway as the Therapeutic Target for Anticancer Traditional Chinese Medicines

“…Oridonin also synergistically increased the cytotoxicity of Nutlin-3 [an inhibitor of murine double minute 2 (Mdm2)] against wild-type p53 osteosarcoma U2OS cells by enhancing cellular apoptosis via increasing the level of proapoptotic factor Bim and decreasing the levels of antiapoptotic factors Bcl-2 and Bcl-xl (Wang X. H. et al, 2017). Furthermore, oridonin also significantly increased the cytotoxicity and/or reversed drug resistance of various anticancer drugs such as cisplatin, gemcitabine, and lentinan by downregulation of Bcl2 expression and upregulation of Bax expression in multiple human cancer cell lines including ovarian, pancreatic, and liver cancers (Liu D. L. et al, 2014; Ma et al, 2016; Xu T. et al, 2017).…”

n‐6 and n‐3 Fatty acids and their metabolites augment inhibitory action of doxorubicin on the proliferation of human neuroblastoma (IMR‐32) cells by enhancing lipid peroxidation and suppressing Ras, Myc, and Fos

“…Human β-actin was chosen as the active control. The expression of various genes was measured by qRT-PCR as described previously [36][37][38][39][40][41][42][43]. On completion of PCR, products of each gene processed were separated by means of an electric field at 100 V and size on 1.5% agarose gels in 1 × TAE buffer, stained with ethidium bromide.…”