BBA, a Synthetic Derivative of 23-hydroxybutulinic Acid, Reverses Multidrug Resistance by Inhibiting the Efflux Activity of MRP7 (ABCC10)

Abstract

Natural products are frequently used for adjuvant chemotherapy in cancer treatment. 23-O-(1,4'-bipiperidine-1-carbonyl) betulinic acid (BBA) is a synthetic derivative of 23-hydroxybutulinic acid (23-HBA), which is a natural pentacyclic triterpene and the major active constituent of the root of Pulsatilla chinensis . We previously reported that BBA could reverse P-glycoprotein (P-gp/ABCB1)-mediated multidrug resistance (MDR). In the present study, we investigated whether BBA has the potential to reverse multidrug resistance protein 7 (MRP7/ABCC10)-mediated MDR. We found that BBA concentration-dependently enhanced the sensitivity of MRP7-transfected HEK293 cells to paclitaxel, docetaxel and vinblastine. Accumulation and efflux experiments demonstrated that BBA increased the intracellular accumulation of [3H]-paclitaxel by inhibiting the efflux of [3H]-paclitaxel from HEK293/MRP7 cells. In addition, immunoblotting and immunofluorescence analyses indicated no significant alteration of MRP7 protein expression and localization in plasma membranes after treatment with BBA. These results demonstrate that BBA reverses MRP7-mediated MDR through blocking the drug efflux function of MRP7 without affecting the intracellular ATP levels. Our findings suggest that BBA has the potential to be used in combination with conventional chemotherapeutic agents to augment the response to chemotherapy.

FTY720 enhances chemosensitivity of colon cancer cells to doxorubicin and etoposide via the modulation of P‐glycoprotein and multidrug resistance protein 1

“…We presumed that, other than downregulating mRNA expression, other mechanisms such as ATPase activity modulation and intracellular ATP changes might be involved. It has also been reported that some substances, such as vitamin E, can reverse the activity of MDR transporters without affecting their expressions . Interestingly, we found that 20 μmol/L FTY720 had no apparent effect on modulating P‐gp activity or its mRNA expression, this might be attributed to the complex relationship between FTY720 and ceramide.…”

Betulinic Acid and its Derivatives as Potential Antitumor Agents

“…Our group found that BBA, a derivative of 23‐HBA, can significantly reverse the MDR of ABCB1 overexpressing cells by interacting directly with ABCB1 and greatly affecting the ABCB1 ATPase activity to block the transport function of ABCB1 . Further investigation found that BBA shows potential ability to reverse ABCC10 (MRP7)‐mediated MDR by inhibiting its efflux activity …”

“…130 Further investigation found that BBA shows potential ability to reverse ABCC10 (MRP7)-mediated MDR by inhibiting its efflux activity. 131 Furthermore, two bipiperidinyl derivatives of 23-HBA, DABB (3,23-O-diacetyl-17-1,4'bipiperidinyl betulinic amide), and DHBB (3,23-O-dihydroxy-17-1,4'-bipiperidinyl betulinic amide) can also reverse MDR mediated by ATP-binding cassette transporter. We found that DABB or DHBB exhibits its potent ABCB1 ATPase suppression characteristics at nontoxic concentrations, rather than by altering mRNA and protein of ABCB1.…”

Betulinic Acid: Recent Advances in Chemical Modifications, Effective Delivery, and Molecular Mechanisms of a Promising Anticancer Therapy

“…Some BetA analogs exhibited strong inhibitory activity for topoisomerase I and IIα by suppressing its activity, without interfering with the cell death mechanism of BetA. However, small differences in the structure can alter the mechanisms of action .…”

“…In this context, antiangiogenic ranibizumab has already become a first-line therapy for wet macular degeneration (142). Some BetA analogs exhibited strong inhibitory activity for topoisomerase I and IIa (32,(143)(144)(145) by suppressing its activity, without interfering with the cell death mechanism of BetA. However, small differences in the structure can alter the mechanisms of action.…”