SYNTHESIS OF NOVEL NAPHTHOQUINONE AND ISOQUINOLINE-5,8-QUINONE-4-OXOQUINOLINE DERIVATIVES TARGETING AMPK AND UPR PATHWAYS IN BREAST CANCER CELLS
Vol 1, 2020 - 132383
DR - Doctoral Student
Abstract
Cancer is one of the leading causes of public health system problem worldwide and its incidence is increasing in the world. Cancer can acquire resistance to traditional treatments, such as chemo and radiotherapy. The UPR represents an adaptative response to the inhospitable microenvironment in which tumor cells are. AMPK activation represents an adaptative response and it inhibits endoplasmic reticulun stress (ERS) and the unfolded protein response (UPR), leading to cell death. Quinones are a wide class of compounds found in nature which already have anticancer activity, such as the induction of apoptosis and the increased production of reactive oxygen species (ROS). The objective of the following study is to investigate the anticancer activity of two quinone hybrids and to evaluate its mechanism of action. Isoquinoline-quinone derivatives were synthesized at Professor Maria Cecília´s laboratory. For biological studies MCF-7 and MCF10A were used. We assessed cell viability, cell death mechanism, glucose consumption, lactate production, intracellular ATP content, ROS production, autophagy and endoplasmic reticulum stress. We found that compound 13a was efficient at reducing cell viability with no reversible effect. Also, it reduced glucose consumption, lactate production and intracellular ATP content. As a consequence of reduced intracelluar ATP content, AMPK was activated with reduced p70S6K activation, even though mTOR did not present a decreased activity. These effects were observed on MCF-7 cells, but not in MCF10A cells. Another consequence of AMPK activation was reduced ERS with decreased PERK activation. After a dorsomorphin treatment, a AMPK inhibitor, PERK activation was increased, so we concluded that PERK inhibition was due to AMPK activation. ROS production was also evaluated and we found increasing levels of ROS after compound 13a tratment. Cell death mechanism was also evaluated and we found increased autophagy. We conclude that compound 13a is a efficient novel molecule with anticancer activity by inducing the activation of AMPK signaling pathway, the inhibition of UPR response, leading to autophagy cell death mechanism.
Institutions
- 1 Universidade Federal do Rio de Janeiro
- 2 Instituto de Química / Universidade Federal Fluminense
Track
- Metabolism and Glycobiology
Keywords
Breast cancer
autophagy
AMPK activation
ER stress
Quinone Hybrids
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Angélica Lauria
Oi Eduardo, muito obrigada.
1) Essas estruturas já demonstram ter atividade antitumoral separadamente, as quinonas com o aumento do estresse oxidativo e as quinolinas com inibição da topoisomerase II e da RNA polimerase I. Assim, nós buscamos avaliar se poderia haver alguma potencialização dos efeitos dessas estruturas quando hibridizados.
2) As estruturas apresentam um mesmo precursor, mas os compostos não apresentam a mesma substituição.
Perdão, não trouxemos esse dado da concentração escolhida em 50uM, mas foi a partir de um screening inicial por MTT, onde observamos a redução da viabilidade da linhagem MCF-7.
3) Eu acredito que há um mecanismo dual, mas pode ser que se tenha um outro mecanismo de ação. Pra isso, teríamos que ter um estudo mais aprofundado em relação a isso.
4) Nós não modulamos a autofagia nem antes, nem durante o tratamento. Nosso objetivo foi avaliar se o composto induziria autofagia tanto quanto a rapamicina. Mas, acredito que se tivéssemos feito essa modulação, talvez, fosse possível observar um aumento na taxa de autofagia para a menor concentração testada (12uM). Obrigada por essa sugestão.