Doxorubicin-conjugated dexamethasone induced MCF-7 apoptosis without entering the nucleus and able to overcome MDR-1-induced resistance

Abstract

BackgroundDoxorubicin (DOX) is the most widely used chemotherapeutic agent that has multimodal cytotoxicity. The main cytotoxic actions of DOX occur in the nucleus. The emergence of drug-resistant cancer cells that have the ability to actively efflux DOX out of the nucleus, and the cytoplasm has led to the search for a more effective derivative of this drug.Materials and methodsWe created a new derivative of DOX that was derived via simple conjugation of the 3′ amino group of DOX to the dexamethasone molecule.ResultsDespite having a lower cytotoxic activity in MCF-7 cells, the conjugated product, DexDOX, exerted its actions in a manner that was different to that of DOX. DexDOX rapidly induced MCF-7 cell apoptosis without entering the nucleus. Further analysis showed that Dex-DOX increased cytosolic oxidative stress and did not interfere with the cell cycle. In addition, the conjugated product retained its cytotoxicity in multidrug resistance-1-overexpressing MCF-7 cells that had an approximately 16-fold higher resistance to DOX.ConclusionWe have synthesized a new derivative of DOX, which has the ability to overcome multidrug resistance-1-induced resistance. This molecule may have potential as a future chemotherapeutic agent.

Nanoencapsulated Doxorubicin Prevents Mucositis Development in Mice

“…DOX is an API widely used in cancer therapy, being effective in treatment of several types of cancer, such as leukemia, Hodgkin’s and non-Hodgkin’s lymphomas and breast cancer [ 8 ]. To be used in the clinic, DOX is formulated as a hydrochloride salt dissolved in an aqueous solution for intravenous injection [ 9 ], being rapidly distributed into tissues [ 10 , 11 ].…”

Influence of dexamethasone and doxorubicin on inhibition of hypoxia- -induced metastatic potential in HepG2 cell line

“…However, some literature reports indicate its inhibiting effect on the migratory potential of cancer cells and blocking the hypoxia-induced EMT process [15]. Furthermore, the combination of DEX and DOX along with other cytostatics has been extensively tested for many types of cancer [16,17] '*' indicate statistically significant differences in comparison to control cells in normoxia, '#' to hypoxia, and '$' between appropriate doses in normoxia and hypoxia (P < 0.05; 2way ANOVA with Dunnett's or Sidak's multiple comparisons test). Data presented as mean ± SD www.journals.viamedica.pl/medical_research_journal 0 0.5 '*' indicate statistically significant differences for control cells in normoxia, '#' in hypoxia, and '$' between appropriate doses in normoxic and hypoxic conditions (P < 0.05; 2way ANOVA with Dunnett's or Sidak's multiple comparisons test).…”

Antitumour Anthracyclines: Progress and Perspectives

“…Dissimilarly to the nuclear activity of the drug, the conjugate promoted apoptosis in the cytoplasm by enhancing oxidative stress without affecting cell cycle and was better absorbed into MCF‐7 cells than doxorubicin using flow cytometry analysis. Despite the weaker cytotoxicity, it was argued that the lower drug resistance index and alternative mechanism of action could make the conjugate an interesting chemotherapeutic agent …”