Abstract
Lysosomes have become a hot topic in tumor therapy; targeting the lysosome is therefore a promising strategy in cancer therapy. Based on our previous lysosome-targeted bio-imaging agent, homospermine-benzo[cd]indol-2(1H)-one conjugate (HBC), we further developed three novel series of polyamine- benzo[cd]indol-2(1H)-one conjugates. Among them, compound 15f showed potent inhibitory activity in hepatocellular carcinoma migration both in vitro and in vivo. Our study results showed that compound 15f entered the cancer cells via the polyamine transporter localized in the lysosomes and caused autophagy and apoptosis. The mechanism of action revealed that the crosstalk between autophagy and apoptosis induced by 15f was mutually reinforcing patterns. Besides, 15f also targeted lysosomes and exhibited stronger green fluorescence than HBC, which indicated its potential as an imaging agent. To summarize, compound 15f could be used as a valuable dual-functional lead compound for future development against liver-cancer metastasis and lysosome imaging.
Highlights
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide owing to its high recurrence rate and poor prognosis [1,2,3]
Our research group has focused on polyamine conjugates for several years; we reported that the antitumor effects of polyamine conjugates were exerted by the induction of autophagy and apoptosis, and found there was a crosstalk between autophagy and apoptosis [19, 20]
To optimize the potency of homospermine-benzo[cd]indol-2(1H)-one conjugate (HBC) and explore its structure-activity relationship (SAR), three series of derivatives were synthesized as shown in Schemes 1, 2
Summary
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide owing to its high recurrence rate and poor prognosis [1,2,3]. Since HCC exhibits no identifiable symptoms at the premorbid stage, a majority of patients with liver cancer are often diagnosed at an advanced stage, which is often accompanied with micro-metastases. In such cases, a surgical resection is Abbreviations: HCC, Hepatocellular carcinoma; CQ, chloroquine; BIO, Benzo[cd]indol-2(1H)-one; HCT-116, human colon cancer; Hela, human cervical carcinoma; HepG2, human hepatoma; HuH-7, human hepatoma; Mito, Mitoxantrone; ALT, glutamic-pyruvic transaminase; AST, glutamic oxalacetic transaminase; TBA, total bile acid; BUN, urea nitrogen; H&E, Hematoxylin and eosin; PPT1, palmitoyl protein thioesterase 1; DC661, dimeric chloroquine; DQ661, dimeric quinacrines; CTSD, cathepsin D; TFEB, Transcription Factor EB; 3-MA, 3-methyladenine; BafA1, Bafilomycin A1; V-ATPase, Vacuolartype ATPase; Cr, creatinine; SAR, structure-activity relationship; HBC, 1-{4-[4-(4-Aminobutylamino)butylamino]butyl]}benzo[cd]indol-2(1H)-one trihydrochloride (homospermine-benzo[cd]indol-2(1H)-one conjugate). It has been reported that several drugs that induce autophagy demonstrate potent anticancer activity [13, 14]
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