Multidrug resistance (MDR) is a serious hurdle to successful cancer therapy. Here,
we examined the efficiency of novel semi-synthetic dihydrotestosterone derivatives,
more specifically androstano-arylpyrimidines in inhibiting the efflux activity of
ATP-binding cassette (ABC) transporters and sensitizing inherently MDR colon cancer
cells to various chemotherapy drugs. Using the Rhodamine123 accumulation assay, we
evaluated the efflux activity of cancer cells following treatments with androstano-arylpyrimidines.
We found that acetylated compounds were capable of attenuating the membrane efflux
of inherently MDR cells; however, deacetylated counterparts were ineffective. To delineate
the possible molecular mechanisms underlying these unique activities of androstano-arylpyrimidines,
the degree of apoptosis induction was assessed by AnnexinV-based assays, both upon
the individual as well as by steroid and chemotherapy agent combination treatments.
Five dihydrotestosterone derivatives applied in combination with Doxorubicin or Epirubicin
triggered massive apoptosis in MDR cells, and these combinations were more efficient
than chemotherapy drugs together with Verapamil. Furthermore, our results revealed
that androstano-arylpyrimidines induced significant endoplasmic reticulum stress (ER
stress) but did not notably modulate ABC transporter expression. Therefore, ER stress
triggered by acetylated androstano-arylpyrimidines is probably involved in the mechanism
of efflux pump inhibition and drug sensitization which can be targeted in future drug
developments to defeat inherently multidrug-resistant cancer.
