Background: Dual-targeting in cancer treatment by a single drug is an unconventional
approach in relation to drug combinations. The rationale for the development of dualtargeting
agents is to overcome incomplete efficacy and drug resistance frequently present
when applying individual targeting agents. Consequently, -a more favorable outcome of cancer
treatment is expected with dual-targeting strategies.
Methods: We reviewed the literature, concentrating on the association between clinically
relevant and/or novel dual inhibitors with the potential to modulate multidrug resistant phenotype
of cancer cells, particularly the activity of P-glycoprotein. A balanced analysis of content
was performed to emphasize the most important findings and optimize the structure of this
Results: Two-hundred and forty-five papers were included in the review. The introductory
part was interpreted by 9 papers. Tyrosine kinase inhibitors’ role in the inhibition of Pglycoprotein
and chemosensitization was illustrated by 87 papers. The contribution of naturalbased
compounds in overcoming multidrug resistance was reviewed using 92 papers, while
specific dual inhibitors acting against microtubule assembling and/or topoisomerases were
described with 55 papers. Eleven papers gave an insight into a novel and less explored approach
with hybrid drugs. Their influence on P-glycoprotein and multidrug resistance was
Conclusion: These findings bring into focus rational anticancer strategies with dual-targeting
agents. Most evaluated synthetic and natural drugs showed a great potential in chemosensitization.
Further steps in this direction are needed for the optimization of anticancer treatment.