Bufalin reverses intrinsic and acquired drug resistance to cisplatin through the AKT signaling pathway in gastric cancer cells

Abstract

Cisplatin is the most common chemotherapeutic agent for gastric cancer (GC), however it activates AKT, which contributes to intrinsic and acquired resistance. Bufalin, a traditional Chinese medicine, shows significant anticancer activity by inhibiting the AKT pathway. It was therefore hypothesized that bufalin could counteract cisplatin resistance in GC cells. SGC7901, MKN‑45 and BGC823 human GC cells were cultured under normoxic and hypoxic conditions. Effects of cisplatin and bufalin on GC cells were measured by a cell counting kit, apoptosis was analyzed by flow cytometry, and immunoblotting was used to detect proteins associated with the AKT signaling pathway. It was demonstrated that bufalin synergized with cisplatin to inhibit proliferation and promote apoptosis of GC cells by diminishing the activation of cisplatin-induced AKT under normoxic and hypoxic conditions. Bufalin also inhibits cisplatin-activated molecules downstream of AKT that affect proliferation and apoptosis, including glycogen synthase kinase, mammalian target of rapamycin, ribosomal protein S6 Kinase and eukaryotic translation initiation factor-4E-binding protein-1. To investigate acquired cisplatin resistance, a cisplatin‑resistant cell line SGC7901‑CR was used. It was demonstrated that bufalin reversed acquired cisplatin resistance and significantly induced apoptosis through the AKT pathway. These results imply that bufalin could extend the therapeutic effect of cisplatin on GC cells when administered in combination.

Response prediction to oxaliplatin plus 5‑fluorouracil chemotherapy in patients with colorectal cancer using a four‑protein immunohistochemical model

“…Previous studies revealed that MAPK signaling pathway activation serves key roles in drug resistance, notably in gastric cancer, breast cancer, prostate cancer and CRC. The PI3K/AKT/mTOR pathway also regulates cancer progression and is recognized as a major cause of multidrug resistance in various types of cancer (15)(16)(17)(18). This pathway has also been identified as a potent contributor to drug resistance in CRC, particularly resistance to 5-FU and oxaliplatin (35).…”

“…Oxaliplatin plus 5-FU regimen resistance is subsequently induced via the activation of the PI3K/AKT, MAPK and Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling pathways. In addition, it has been reported that the MAPK (12)(13)(14) and PI3K/AKT/mTOR (15)(16)(17)(18) pathways serve key roles in drug resistance, notably in CRC, and that PI3K/AKT signaling pathway inhibition can reduce resistance to chemotherapeutic drugs. It was also reported that survivin overexpression, which may be a downstream effect of the MAPK or PI3K-AKT-mTOR signaling pathway (19), is associated with drug resistance in CRC.…”

Bufalin reverses acquired drug resistance by inhibiting stemness in colorectal cancer cells

“…We found that drug resistance was higher in STSCs cis than in their parent cells, which proved that cisplatin could induce acquired drug resistance. In view of the inhibiting stemness and acquired drug-resistance effects (23), we speculated that bufalin could inhibit acquired cisplatin resistance in CRC cells via the inhibition of stemness. We found that the combination of bufalin and cisplatin could inhibit proliferation and induce apoptosis in STSCs cis in vitro .…”

“…In the past decade, bufalin was shown to possess high anticancer ability in various cancers (20–24). The anticancer mechanisms of bufalin can be summarized as: inhibition of proliferation (20), promotion of apoptosis (24), inhibition of angiogenesis and metastasis (21), reversal of drug resistance (23), and induction of autophagy (25). Recent studies have suggested that bufalin inhibits differentiation, proliferation, and drug resistance in cancers via the inhibition of stemness (26–28).…”

Bufalin inhibits gastric cancer invasion and metastasis by down-regulating Wnt/ASCL2 expression

“…For example, bufalin can inhibit cancer cell proliferation [ 5 , 6 ], induce cancer cell apoptosis and autophagy [ 7 , 8 ], inhibit cancer metastasis and invasion [ 9 , 10 ], and reverse multidrug resistance [ 11 ]. Studies had found that bufalin inhibits GC proliferation, induces apoptosis, and reverses cisplatin resistance [ 12 , 13 ]. However, the anti-invasion and anti-metastasis activity of bufalin in GC is still not clear.…”