ABCB1 and ABCG2 Overexpression Mediates Resistance to the Phosphatidylinositol 3-Kinase Inhibitor HS-173 in Cancer Cell Lines

Constitutive activation of the phosphoinositide-3-kinase (PI3K)/Akt signaling pathway is crucial for tumor growth and progression. As such, this pathway has been an enticing target for drug discovery. Although HS-173 is a potent PI3K inhibitor that halts cancer cell proliferation via G2/M cell cycle arrest, the resistance mechanisms to HS-173 have not been investigated. In this study, we investigated the susceptibility of HS-173 to efflux mediated by the multidrug efflux transporters ABCB1 and ABCG2, which are two of the most well-known ATP-binding cassette (ABC) transporters associated with the development of cancer multidrug resistance (MDR). We found that the overexpression of ABCB1 or ABCG2 significantly reduced the efficacy of HS-173 in human cancer cells. Our data show that the intracellular accumulation of HS-173 was substantially reduced by ABCB1 and ABCG2, affecting G2/M arrest and apoptosis induced by HS-173. More importantly, the efficacy of HS-173 in multidrug-resistant cancer cells could be recovered by inhibiting the drug-efflux function of ABCB1 and ABCG2. Taken together, our study has demonstrated that HS-173 is a substrate for both ABCB1 and ABCG2, resulting in decreased intracellular concentration of this drug, which may have implications for its clinical use.

 

Comments:

The study you described focuses on investigating the resistance mechanisms to the potent phosphoinositide-3-kinase (PI3K) inhibitor, HS-173, which has shown effectiveness in halting cancer cell proliferation through G2/M cell cycle arrest. The researchers specifically examined the role of two multidrug efflux transporters, ABCB1 and ABCG2, in mediating the efflux of HS-173.

ABCB1 and ABCG2 are ATP-binding cassette (ABC) transporters that are commonly associated with the development of multidrug resistance (MDR) in cancer. These transporters play a crucial role in pumping various drugs out of cancer cells, thereby reducing their intracellular concentrations and limiting their therapeutic efficacy.

The researchers found that overexpression of either ABCB1 or ABCG2 led to a significant reduction in the effectiveness of HS-173 in human cancer cells. This reduced efficacy was attributed to the ability of ABCB1 and ABCG2 to actively pump HS-173 out of the cells, resulting in decreased intracellular drug accumulation. Consequently, the G2/M cell cycle arrest and apoptosis induced by HS-173 were impaired.

Importantly, the study also demonstrated that inhibiting the drug-efflux function of ABCB1 and ABCG2 could restore the efficacy of HS-173 in multidrug-resistant cancer cells. By blocking the efflux transporters, the intracellular concentration of HS-173 increased, allowing it to effectively exert its anticancer effects once again.

These findings highlight that HS-173 is a substrate for both ABCB1 and ABCG2, and the efflux activity of these transporters contributes to decreased intracellular drug levels. This information is significant for the clinical use of HS-173, as it suggests that combination strategies involving ABCB1 and ABCG2 inhibitors could enhance the drug's therapeutic effectiveness in multidrug-resistant cancers.

In summary, the study provides insights into the resistance mechanisms associated with HS-173, indicating that the efflux transporters ABCB1 and ABCG2 play a role in reducing intracellular drug accumulation. By inhibiting the drug-efflux function of these transporters, the efficacy of HS-173 can be restored, potentially improving its clinical utility in multidrug-resistant cancer cases.