The palladacycle, BTC2, exhibits anti-breast cancer and breast cancer stem cell activity

Autor(es):Mostrar menos -

Kimani, Serah ^[1] ; Chakraborty, Suparna ^[1] ; Irene, Ikponmwosa ^[1] ; de la Mare, Jo ^[2] ; Edkins, Adrienne ^[2] ; du Toit, Andre ^[3] ; Loos, Ben ^[3] ; Blanckenberg, Angelique ^[4] ; Van Niekerk, Annick ^[4] ; Costa-Lotufo, V, Leticia ; ArulJothi, K. N. ^{[1, 5]} ; Mapolie, Selwyn ^[4] ; Prince, Sharon ^[1]

Afiliação do(s) autor(es)

^[1] Univ Cape Town, Fac Hlth Sci, Dept Human Biol, Div Cell Biol, Cape Town, Western Cape - South Africa

^[2] Rhodes Univ, Dept Biochem Microbiol & Biotechnol, Biomed Biotechnol Res Unit, Grahamstown - South Africa

^[3] Stellenbosch Univ, Dept Physiol Sci, Stellenbosch, Western Cape - South Africa

^[4] Stellenbosch Univ, Dept Chem & Polymer Sci, Stellenbosch, Western Cape - South Africa

^[5] SRM Inst Sci & Technol, Dept Genet Engn, Chennai, Tamil Nadu - India

• Tipo de documento: Artigo Científico
• Fonte: Biochemical Pharmacology; v. 190, AUG 2021.
• Citações Web of Science: 0

Resumo

In women globally, breast cancer is responsible for most cancer-related deaths and thus, new effective therapeutic strategies are required to treat this malignancy. Platinum-based compounds like cisplatin are widely used to treat breast cancer, however, they come with limitations such as poor solubility, adverse effects, and drug resistance. To overcome these limitations, complexes containing other platinum group metals such as palladium have been studied and some have already entered clinical trials. Here we investigated the anti-cancer activity of a palladium complex, BTC2, in MCF-7 oestrogen receptor positive (ER+) and MDA-MB-231 triple negative (TN) human breast cancer cells as well as in a human breast cancer xenograft chick embryo model. BTC2 exhibited an average IC50 value of 0.54 mu M, a desirable selectivity index of >2, inhibited the migration of ER+ and TN breast cancer cells, and displayed anti-cancer stem cell activity. We demonstrate that BTC2 induced DNA double strand breaks (increased levels of gamma-H2AX) and activated the p-ATM/p-CHK2 and p-p38/MAPK pathways resulting in Sand G2/M-phase cell cycle arrests. Importantly, BTC2 sensitised breast cancer cells by triggering the intrinsic (cleaved caspase 9) and extrinsic (cleaved caspase 8) apoptotic as well as necroptotic (p-RIP3 and p-MLKL) cell death pathways and inhibiting autophagy and its pro-survival role. Furthermore, in the xenograft in vivo model, BTC2 displayed limited toxicity and arrested the tumour growth of breast cancer cells over a 9-day period in a manner comparable to that of the positive control drug, paclitaxel. BTC2 thus displayed promising anti-breast cancer activity. (AU)

• Processo FAPESP: 19/02008-5 - Substâncias marinhas que induzem dano ao DNA e inibem o TBX2 como uma nova estratégia para tratar câncer de mama
• Beneficiário: Leticia Veras Costa Lotufo
• Modalidade de apoio: Auxílio à Pesquisa - Pesquisador Visitante - Internacional