Emodin reverses gemcitabine resistance in pancreatic cancer cells via the mitochondrial apoptosis pathway in vitro

Abstract

Gemcitabine resistance is a common problem of pancreatic cancer chemotherapy, and how to reverse it plays an important role in the treatment of pancreatic cancer. This study investigated the effect of emodin on the gemcitabine-resistant pancreatic cancer cell line SW1990/Gem, and explored the potential mechanism of its action. SW1990/Gem was obtained by culture of the pancreatic cancer cell line SW1990 in vitro by intermittently increasing the concentration of gemcitabine in the culture medium for 10 months, observing the morphology using inverted microscopy. SW1990/Gem cells were pretreated with emodin (10 μM) for different periods followed by treatment with gemcitabine (20 μM) for 48 h; cell proliferation was tested by MTT assay. SW1990/Gem cells were treated by emodin with different concentrations for 48 h, cell apoptosis was detected by flow cytometry (FCM). The expression of gene and protein, such as MDR-1 (P-gp), NF-κB, Bcl-2, Bax, cytochrome-C (cytosol), caspase-9 and -3 were measured by RT-PCR and Western blotting. The function of P-gp in SW1990/Gem cells was checked by FCM. The results showed that the SW1990/Gem cells changed greatly in morphology and the resistance index was 48.63. Emodin promoted cell apoptosis of the gemcitabine-resistant cell line SW1990/Gem in a dose-dependent manner. Emodin enhanced the SW1990/Gem cell sensitivity to gemcitabine in a time-dependent manner. Emodin monotherapy or combination with gemcitabine both decreased the gene and protein expression levels of MDR-1 (P-gp), NF-κB and Bcl-2 and inhibited the function of P-gp, but increased the expression levels of Bax, cytochrome-C (cytosol), caspase-9 and -3, and promoted cell apoptosis. This demonstrated that emodin had a reversing effect on the gemcitabine-resistant cell line SW1990/Gem, possibly via decreasing the function of P-gp and activating the mitochondrial apoptosis pathway in vitro.

Anti-tumor effect of emodin on gynecological cancer cells

“…Emodin has also been shown to enhance the activity of gemcitabine-mediated pro-apoptosis in pancreatic cancer cells via Akt inhibition and NF-kappaB activation, thus promoting the mitochondria-dependent apoptotic pathway [42]. In the pancreatic cancer cell line SW1990E, emodin was found to induce apoptosis by significantly downregulating NF-kappaB DNA-binding activity, and survivin and MMP-9 expression in SW1990 cells [43][44][45]. Moreover, the expression of cleaved-caspase-3 was found to be upregulated in SW1990 cells after emodin treatment [15].…”

Emodin and Its Combination with Cytarabine Induce Apoptosis in Resistant Acute Myeloid Leukemia Cells in Vitro and in Vivo

“…The administration of emodin in pregnant mice has been previously reported, which indicated its high safety [24]. Liu et al showed that emodin could be used as a sensitizer in the gemcitabine-resistant pancreatic cancer cells [25]. HL-60/ADR cells overexpressed multidrug resistance-associated protein (MRP1) are highly resistant to different chemotherapeutic agents [13,26].…”

Triggering of Erythrocyte Cell Membrane Scrambling by Emodin

“…Molecular mechanisms involved include tyrosine kinases [3,31], casein kinase II [1], protein kinase C [47], AKT/mTOR [1,28,62], NF-κB [1,67,68], HIF-1α [1], STAT3 [1,59], p53 [1,21,23,32,54], Wnt signaling [69], Bcl-2/Bax [21,26,28], mitochondria [38,44,45,49,51,57,63,64], oxidative stress [21,23,32,49,57,61,70], and endoplasmic reticulum stress [38].…”