KPNB1-mediated nuclear import in cancer.

Dysregulation of nucleocytoplasmic shuttling impairs cellular homeostasis and promotes cancer development. KPNB1 is a member of karyopherin ß family, mediating the transportation of proteins from the cytoplasm to the nucleus. In a variety of cancers, the expression of KPNB1 is upregulated to facilitate tumor growth and progression. Both downregulation of KPNB1 level and inhibition of KPNB1 activity prevent the entry of cancer-related transcription factors into the nucleus, subsequently suppressing the proliferation and metastasis of cancer cells. Currently, five KPNB1 inhibitors have been reported and exhibited good efficacy against cancer. This paper provides an overview of the role and mechanism of KPNB1 in different cancers and KPNB1-targeted anticancer compounds which hold promise for the future.

Design, synthesis and biological evaluation of rhein-piperazine-dithiocarbamate hybrids as potential anticancer agents.

A series of novel rhein-piperazine-dithiocarbamate hybrids 3 were efficiently synthesized from rhein through a catalyst-free and one-pot, three-step sequence involving chlorination and N-acylation followed by dithiocarbamate formation. Hybrids 3 were evaluated for their in vitro cytotoxic potency by MTT assay against several human cancer and non-cancer cells. Five of the hybrids were more cytotoxic to human lung cancer cell line A549 than the parent rhein and the reference, cytarabine (CAR). Structure-activity relationship (SAR) analysis indicated that cytotoxicity was significantly enhanced when ester groups were incorporated into the hybrids (3h-j). In particular, hybrid 3h (IC50 = 10.93 µg/mL), containing a long-chain alkyl ester, was the most potent compound toward A549 tumor cells, being 7- and 5-fold more toxic than rhein (IC50 = 77.11 µg/mL) and CAR (IC50 = 49.27 µg/mL), respectively. Additionally, hybrid 3h was less toxic to the corresponding normal human lung fibroblast cell line, WI-38, with a higher selectivity index (SI, WI-38/A549 ≈ 5) than doxorubicin (DOX, SI ≈ 0), CAR (SI ≈ 2) and rhein (SI ≈ 1). Furthermore, hybrid 3h displayed more toxicity against four types of lung cancer cells (A549, Calu-1, PC-9, and H460; IC50 = 10.81-23.78 µg/mL) than against six other types of cancer cells (Huh-7, 786-O, HCT116, Hela, SK-BR-3, and SK-OV-3; IC50 = 23.85-51.98 µg/mL). Further mechanistic studies showed that hybrid 3h induced apoptosis in a concentration-dependent manner in human lung adenocarcinoma cell line PC-9. In vivo safety studies showed that hybrid 3h had no acute toxicity to the major organs of mice and did not lead to blood biochemical index changes. Our results exhibit prominent anti-cancer cell inhibition ability and no obvious systemic toxicity to normal organs, indicating that hybrid 3h has promising potential for further applications in anti-lung cancer drug development.