In vitromodulation of multidrug resistance by pregnane steroids andin vivoinhibition of tumour development by 7α-OBz-11α(R)-OTHP-5β-pregnanedione in K562/R7 and H295R cell xenografts

Abstract

Synthetic progesterone and 5α/β-pregnane-3,20-dione derivatives were evaluated as in vitro and in vivo modulators of multidrug-resistance (MDR) using two P-gp-expressing human cell lines, the non-steroidogenic K562/R7 erythroleukaemia cells and the steroidogenic NCI-H295R adrenocortical carcinoma cells, both resistant to doxorubicin. The maximal effect in both cell lines was observed for 7α- O -benzoyloxy,11α(R)- O -tetrahydropyranyloxy-5β-pregnane-3,20-dione 4 . This modulator co-injected with doxorubicin significantly decreased the tumour size and increased the survival time of immunodeficient mice xenografted with NCI-H295R or K562/R7 cells.

Reversal Effect of Dihydromyricetin on Multiple Drug Resistance in SGC7901/5-FU Cells

“…P-gp, a glycoprotein with 170-kDa molecular weight encoded by the MDR1 gene and consists of 12 transmembrane domains. P-gp plays an important role to pump various chemotherapeutic agents out of MDR carcinoma cells, including the following drugs: taxanes, Vinca alkaloids, anthracyclines, and epipodophyllotoxins (Sarkadi et al, 2006;Alameh et al, 2019;Qiu et al, 2019;Liu et al, 2010;Lopez-Chavez et al, 2009). The overexpression of P-gp endows cancer cell with MDR, thus various approaches were performed to investigate the decreasement of the P-gp expression and the inhibition or modulation of the P-gp activity (Alameh et al, 2019;Qiu et al, 2019).…”

“…P-gp plays an important role to pump various chemotherapeutic agents out of MDR carcinoma cells, including the following drugs: taxanes, Vinca alkaloids, anthracyclines, and epipodophyllotoxins (Sarkadi et al, 2006;Alameh et al, 2019;Qiu et al, 2019;Liu et al, 2010;Lopez-Chavez et al, 2009). The overexpression of P-gp endows cancer cell with MDR, thus various approaches were performed to investigate the decreasement of the P-gp expression and the inhibition or modulation of the P-gp activity (Alameh et al, 2019;Qiu et al, 2019). Recently many reports focus on the application of natural product such as flavonols or flavonoids, results demonstrated they had the decreased effect in the gene expression of multidrug resistance gene-1 (MDR1), and inhibit the transport activity and the of P-gp as well as the P-gp mediated drug efflux, consequently increase the intracellular concentration and cytotoxicity of chemotherapeutic agents, thus effectively reverse the resistance of MDR carcinoma cells in vitro (Liu et al, 2010;Lopez-Chavez et al, 2009).…”

Insights on the Role of Polyphenols in Combating Cancer Drug Resistance

“…While RU486 (an antiprogestin) is a powerful modulator in the lab, its hormone characteristics make it potentially dangerous in humans [ 103 ]. Clinical trials have been conducted using hydrophobic antiestrogens such as tamoxifen and its variants to treat breast cancer; however, because these compounds act as growth agonists in some uterine cells, they may increase the risk of endometrial cancer [ 104 , 105 ]. Inhibitors of growth factors and protein kinase C are two novel experimental techniques that have the potential to prevent or postpone the development of membrane transport-associated resistance [ 106 ].…”

Progestins as Anticancer Drugs and Chemosensitizers, New Targets and Applications

“…Many studies have been devoted to progesterone and its analogs as modulators of P-gp mediated resistance of tumor cells [ 66 , 67 , 68 , 69 ]. Moreover, to date, there is convincing evidence of the specific action of progesterone on P-glycoprotein [ 70 ].…”