DEVELOPMENT OF NOVEL UNCONVENTIONAL CELL DEATH INDUCERS AGAINST TRIPLE NEGATIVE BREAST CANCER

Saloni Malla; Shikha Kumari; David Terrero; Dayanidhi Raman; Aniruddha Ray; Piyush Trivedi; Amit Tiwari

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Trabajo

Título del Trabajo

DEVELOPMENT OF NOVEL UNCONVENTIONAL CELL DEATH INDUCERS AGAINST TRIPLE NEGATIVE BREAST CANCER

Autores

Saloni Malla
Shikha Kumari
David Terrero
Dayanidhi Raman
Aniruddha Ray
Piyush Trivedi
Amit Tiwari

Modalidad

Resúmenes

Área temática

Biología molecular (Ciencias ómicas, Bioinformática y Filogenia)

Fecha de publicación

16/03/2023

País de publicación

República Dominicana

Idioma de la Publicación

Espanhol

Página del Trabajo

https://www.even3.com.br/anais/xviicic2022/501828-development-of-novel-unconventional-cell-death-inducers-against-triple-negative-breast-cancer

ISBN

978-85-5722-646-3

Palabras Clave

unconventional

Resumen

Metastatic breast cancer with triple-negative status (TNBC) is the most aggressive subtype with poor prognosis. Taxanes and/or anthracyclines, currently used for neoadjuvant chemotherapy against TNBC, show an initial response, but they are followed by drug resistance, relapse, side effects and a tendency to metastasize. In recent studies, it has been shown that targeting mitochondrial dynamics, a process that is now associated with the initiation, progression, and metastasis of TNBC, is an effective therapeutic approach. TNBC is characterized by upregulation of mitochondrial fission factors such as Dynamin-related protein 1 (Drp1), which affects mitochondrial energetics and alters metabolism, promoting tumor growth. The use of molecules that specifically target Drp1 as a promising treatment option for TNBC was designed and developed by us. In recent years, we identified a new class of structurally constrained thienopyridine (TPH) probes, including the new analog, TPH104c, that demonstrated higher binding affinity to Drp1 than the weak Drp1 inhibitor, Mdivi-1. Surface plasmon resonance was used to validate the Drp1 binding affinity of TPH104c. Additionally, western blotting analysis and immunofluorescence analysis confirmed that TPH104c significantly reduced Drp1 fission protein total and phosphorylated forms in MDAMB-231 and BT-20 cells. The inhibition of Drp1 by TPH104c in TNBC cells led to a previously unknown non-apoptotic form of cell death independent of caspases and reactive oxygen species (ROS). An apoptotic cell shrinks rather than forms blebs, which are classical characteristics of apoptosis. The TPH104c treated cells were enlarged, round, and swollen. The cells lost their ability to proliferate and were significantly less confluent than control cells. Additionally, TPH104c treated cells did not lose mitochondrial membrane potential, or activate caspase, and when incubated with pan-caspase inhibitor, the cell death was not reversed. Currently, other studies are underway to understand how Drp1 inhibition leads to non-apoptotic cell death, which will assist in optimizing an effective lead compound for the future preclinical development of TNBC anticancer agents.

Título del Evento: Semana Dominicana de Ciencia y Tecnología / XVII CONGRESO INTERNACIONAL DE INVESTIGACIÓN CIENTÍFICA (XVII CIC)
Ciudad del Evento: Santo Domingo
Título de las Actas del Evento: XVII Congreso Internacional de Investigación Científica- Semana Dominicana de Ciencia y Tecnología
Nombre de la Editora: Even3
Medio de Divulgación: Meio Digital

Como citar

MALLA, Saloni et al.. DEVELOPMENT OF NOVEL UNCONVENTIONAL CELL DEATH INDUCERS AGAINST TRIPLE NEGATIVE BREAST CANCER.. In: XVII Congreso Internacional de Investigación Científica- Semana Dominicana de Ciencia y Tecnología. Anais...Recife(PE) Santo Domingo, 2022. Disponible en: https//www.even3.com.br/anais/XVIICIC2022/501828-DEVELOPMENT-OF-NOVEL-UNCONVENTIONAL-CELL-DEATH-INDUCERS-AGAINST-TRIPLE-NEGATIVE-BREAST-CANCER. Acceso en: 01/06/2025