Molecular Simulations Identify Target Receptor Kinases Bound by Astaxanthin to Induce Breast Cancer Cell Apoptosis

Background: We investigated molecular mechanisms behind astaxanthinmediatedinduction of apoptosis in breast cancer cell lines toward combinationtherapy against cancer drug resistance. Methods: Breast cancer cell lines were treated with serial concentrations ofastaxanthin to determine its IC۵۰. We used drug-design software to predictinteractions between astaxanthin and receptor tyrosine kinases or other key geneproducts involved in intracellular signaling pathways. Changes in gene expressionwere examined using RT-PCR. The effect of astaxanthin-nanocarbonscombinations on cancer cells was also evaluated. Results: Astaxanthin induced cell death in all three breast cancer cell lines wasexamined so that its IC۵۰ in two HER۲-amplifying lines SKBR۳ and BT-۴۷۴stood, respectively, at ۳۶ and ۳۷ μM; however, this figure for MCF-۷ wassignificantly lowered to ۲۳ μM (P<۰.۰۵). Astaxanthin-treated SKBR۳ cellsshowed apoptotic death upon co-staining. Our in silico examinations showed thatsome growth-promoting molecules are strongly bound by astaxanthin via theirspecific amino acid residues with their binding energy standing below -۶KCa/Mol. Next, astaxanthin was combined with either graphene oxide orcarboxylated multi-walled carbon nanotube, with the latter affecting SKBR cellsurvival more extensively than the former (P<۰.۰۵). Finally, astaxanthin coinducedtumor suppressors p۵۳ and PTEN but downregulated the expression ofgrowth-inducing genes in treated cells.Conclusions: These findings indicate astaxanthin carries' multitarget antitumorigeniccapacities and introduce the compound as a suitable candidate forcombination therapy regimens against cancer growth and drug resistance.Development of animal models to elucidate interactions between the compoundand tumor microenvironment could be a major step forward towards the inclusionof astaxanthin in cancer therapy trials.

Keywords:

Breast cancer , astaxanthin , apoptosis , receptor tyrosine kinase