Reversal of P-glycoprotein-mediated multidrug resistance by novel curcumin analogues in paclitaxel-resistant human breast cancer cells

Abstract

<jats:p> Multidrug resistance (MDR) is a major obstacle for successful cancer chemotherapy, and the main cause of MDR has been attributed to overexpression of P-glycoprotein (P-gp). In this present study, four P-gp modulators (E,E)-4,6-bis(styryl)-2-(substituted amino)-pyrimidines were evaluated for their activity in a breast cancer cell line overexpressing P-gp (LCC6MDR). The four modulators displayed significantly better P-gp modulating activity compared with the positive control verapamil (RF = 5.4), with a relative fold (RF) increase in activity ranging from 33.3 to 86.0. In contrast to compounds a and c that exhibited lower cytotoxicity, compounds b and d were nontoxic towards both cancer cells and normal cells, with IC<jats:sub>50</jats:sub> values greater than 100 μmol/L. The qRT-PCR results demonstrated that after exposure to 2 μmol/L of compounds a, b, c, and d, the mRNA expression level of MDR1 in LCC6MDR cells decreased to 45%, 50%, 38%, and 51%, respectively. However, the Western-blot results indicated that compound c could reverse P-gp mediated MDR, but not via decreases in protein expression. DOX and Rh123 accumulation and efflux results further confirmed that the reversal of MDR activity happens via inhibition of P-gp efflux and increases in intracellular drug accumulation. These results demonstrated that compound c has low toxicity and is an efficient P-gp modulator, highlighting its potential as a promising candidate for P-gp-mediated reversal of MDR. </jats:p>

Mechanisms of Taxane Resistance

“…Substantial evidence exists for the role of P-gp in mediating taxane resistance in vitro; however, demonstrating its role in vivo has proven more difficult [61][62][63]. Nevertheless, ongoing research continues to explore the possibility of P-gp inhibition as a sufficient means for overcoming taxane resistance in vivo.…”

Recent advances and future directions in anti‐tumor activity of cryptotanshinone: A mechanistic review

“…Even considering that natural anti-tumor drugs have lower potential compared to synthetic antitumor drugs, it has been shown that plant derived-natural compounds can be considered as adjuvants in cancer therapy along with other chemotherapeutic agents (Chen, Gao, Zhang, Chan, & Wong, 2019; Gokce Kutuk, Gokce, Kutuk, Gurses Cila, & Naziroglu, 2019). It is worth mentioning that naturally occurring compounds are able to sensitize cancer cells into chemotherapy-mediated apoptosis and cell cycle arrest (Gao et al, 2020;Zhao et al, 2019). So, plant derivednatural compounds are potential and beneficial compounds in cancer therapy.…”

1-Chromonyl-5-Imidazolylpentadienone Demonstrates Anti-Cancer Action against TNBC and Exhibits Synergism with Paclitaxel

“…Moreover, the migration of MDA-MB-231 cells was significantly reduced by the combination of KY-20-22 and paclitaxel compared to individual treatment ( Figure 8 A). Furthermore, various studies reported that curcumin and its analogs increase sensitivity to chemotherapeutic drugs by reversing the multidrug resistance of cancer cells [ 50 , 51 ]. The combined action of paclitaxel and KY-20-22 on TNBC cells may be due to the action of KY-20-22 on multidrug resistance proteins.…”