Quercetin potentializes the respective cytotoxic activity of gemcitabine or doxorubicin on 3D culture of AsPC-1 or HepG2 cells, through the inhibition of HIF-1α and MDR1

Abstract

The impact of cancer on lifespan is significantly increasing worldwide. Enhanced activity of drug efflux pumps and the incidences of the tumor microenvironment such as the apparition of a hypoxic gradient inside of the bulk tumor, are the major causes of chemotherapy failure. For instance, expression of Hypoxia-inducible factor (HIF-1α) has been associated with metastasis, resistance to chemotherapy and reduced survival rate. One of the current challenges to fight against cancer is therefore to find new molecules with therapeutic potential that could overcome this chemoresistance. In the present study, we focused on the bioactive plant flavonoid quercetin, which has strong antioxidant and anti-proliferative properties. We examined the efficacy of combined treatments of quercetin and the anti-cancer drugs gemcitabine and doxorubicin, known to specifically act on human pancreatic and hepatic cancer cells, respectively. Moreover, our study aimed to investigate more in-depth the implication of the multidrug transporter MDR1 and HIF-1α n chemoresistance and if quercetin could act on the activity of the drug efflux pumps and the hypoxia-associated effects. We observed that the anti-cancer drugs, were more effective when administered in combination with quercetin, as shown by an increased percentage of dead cells up to 60% in both 2D and 3D cultures. In addition, our results indicated that the combination of anti-cancer drugs and quercetin downregulated the expression of HIF-1α and increased the expression levels of the regulator of apoptosis p53. Moreover, we observed that quercetin could inhibit the efflux activity of MDR1. Finally, our in vitro study suggests that the efficiency of the chemotherapeutic activity of known anti-cancer drugs might be significantly increased upon combination with quercetin. This flavonoid may therefore be a promising pharmacological agent for novel combination therapy since it potentializes the cytotoxic activity of gemcitabine and doxorubicin on by targeting the chemoresistance developed by the pancreatic and liver cancer cells respectively.

Pharmacological Mechanisms Underlying the Hepatoprotective Effects of Ecliptae herba on Hepatocellular Carcinoma

“…Many studies have reported that inhibition of HIF1A can significantly inhibit the growth of tumors, including HCC [33,34]. Quercetin, as an effective flavonoid component in EH, combined with specific anticancer drugs can increase the expression of p53 by downregulating the expression of HIF1A, thus inducing an increase in the proapoptotic process of liver cancer cells [35]. In addition, the expression of HIF1A can be regulated by activation of the PI3K-AKT pathway, which can be activated by RTK [36,37].…”

Identifying Active Compounds and Mechanism of Camellia nitidissima Chi on Anti-Colon Cancer by Network Pharmacology and Experimental Validation

“…A total of 84 potential targets were obtained by taking the intersection. The majority of the compounds were flavonoids, such as quercetin, luteolin, kaempferide, and kaempferol, which have long been reported to have significant antitumor activity [ 33 – 36 ]. In this research, only eight compounds were found to meet the requirements of OB ≥30% and DL ≥ 0.18.…”

Application of Quercetin in the Treatment of Gastrointestinal Cancers

“…Moreover quercetin could inhibit the MDR-1 efflux activity. In conclusion, they found quercetin could be administered in combination with GEM or DOX in multidrug resistant pancreatic and hepatic cancers, respectively ( Hassan et al, 2020 ).…”

“…They also evaluated the effects of quercetin on the activity of drug efflux pumps as well as the effects related to hypoxia. Moreover, they investigated the role of multidrug transporters (including MDR) and HIF-1α ( Hassan et al, 2020 ). In their research, they combined quercetin with other anticancer drugs and showed that combination therapy (anticancer drug plus quercetin) had better results than single therapy.…”