RESUMO
Each cell in our body is designed with a self-destructive trigger, and if damaged, can happily sacrifice itself for the sake of the body. This process of self-destruction to safeguard the adjacent normal cells is known as programmed cell death or apoptosis. Cancer cells outsmart normal cells and evade apoptosis and it is one of the major hallmarks of cancer. The cardinal quest for anti-cancer drug discovery (bioactive or synthetic compounds) is to be able to re-induce the so called "programmed cell death" in cancer cells. The importance of bioactive compounds as the linchpin of cancer therapeutics is well known as many effective chemotherapeutic drugs such as vincristine, vinblastine, doxorubicin, etoposide and paclitaxel have natural product origins. The present review discusses various bioactive compounds with known anticancer potential, underlying mechanisms by which they induce cell death and their preclinical/clinical development. Most bioactive compounds can concurrently target multiple signaling pathways that are important for cancer cell survival while sparing normal cells hence they can potentially be the silver bullets for targeting cancer growth and metastatic progression.
RESUMO
PARP inhibitors in combination with other agents are in clinical trial against cancer, but its effect on cancer stem cells (CSCs) is limited. CSCs are responsible for drug resistance, metastasis and cancer relapse due to high DNA repair capacity. Here, we present preclinical effects of Quinacrine (QC) with ABT-888, a PARP inhibitor, on highly metastatic breast cancer stem cells (mBCSCs). An increased level of Adenomatous polyposis coli (APC) was noted after treatment with ABT-888 in QC pre-treated mBCSCs cells. Increased APC physically interacts with PARP-1 and inhibits PARylation causing the non assembly of base excision repair (BER) multiprotein complex, resulting in an irreparable DNA damage and subsequent apoptosis. Knockdown of APC in mBCSCs inhibited DNA damage, increased BER and PARylation, reduces apoptosis while the over-expression of APC in BT20 (APC low expressing) cells reversed the effect. Thus, combination of QC and ABT-888 decreased mBCSCs growth by activating APC and inhibiting BER within the cells.
Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Reparo do DNA/efeitos dos fármacos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Quinacrina/farmacologia , Proteína da Polipose Adenomatosa do Colo/antagonistas & inibidores , Proteína da Polipose Adenomatosa do Colo/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Combinação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Feminino , Humanos , Modelos Biológicos , Metástase Neoplásica , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patologiaRESUMO
Here, we report the p53 dependent mitochondria-mediated apoptotic mechanism of plant derived silver-nanoparticle (PD-AgNPs) in colorectal cancer cells (CRCs). PD-AgNPs was synthesized by reduction of AgNO3 with leaf extract of a medicinal plant periwinkle and characterized. Uptake of PD-AgNPs (ξ - 2.52 ± 4.31 mV) in HCT116 cells was 3 fold higher in comparison to synthetic AgNPs (ξ +2.293 ± 5.1 mV). A dose dependent increase in ROS production, activated JNK and decreased mitochondrial membrane potential (MMP) were noted in HCT116 but not in HCT116 p53(-/-) cells after PD-AgNP exposure. PD-AgNP-mediated apoptosis in CRCs is a p53 dependent process involving ROS and JNK cascade.