Currently, discovery of small-molecule modulators of autophagy has become a popular therapy for cancer treatment. A study from Lu Zhang has discovered and identified a potent late-stage macroautophagy/autophagy inhibitor via inhibiting autophagosome-lysosome fusion, CA-5f.

Autophagy plays essential roles in various normal cellular processes, including cell proliferation, ageing, and to maintain cellular homeostasis. It involved in response to a variety of stress conditions such as starvation, oxidative stress, irradiation, and microbial invasion. Additionally, autophagy has also been found to be over-activated in many kinds of cancers, which led to increasing concerns about using autophagy inhibitors as potential anti-tumor agents.

Usually, autophagy inhibitors make up of two categories. One category targets the early stage of autophagy to suppress autophagy induction, such as 3-methyladenine (3-MA), LY294002 and SBI-0206965. The other category of autophagy inhibitors blocks autophagosome-lysosome fusion and/or inhibits autolysosome degradation. For instance, chloroquine (CQ), bafilomycin A1, ARN5187, KB-R7943 are described as before. However, most of the inhibitors couldn’t enter into clinical trials due to their high toxicity.

In the study, the authors carried a series of experiments both in vitro and in vivo.

As a result, in vitro, CA-5f (0-40 μM, 6 hour) concentration- and time-dependently elevated the level of LC3B-II (a marker to monitor autophagy) and SQSTM1 protein both in A549 cells and HUVECs.

Besides, CA-5f (20 μM, 6 hours) inhibited the degradation of autophagosomes when treated alone or in combination Bafilomycin A1 (100 nM) or Chloroquine (30 μM) in A549 cells and

HUVECs.Howeve, CA-5f (20 μM) neither impairs the hydrolytic function nor the quantity of lysosomes.

Importantly, CA-5f (20 μM, 96 hours) inhibits the growth of A549 cells, and less cytotoxic to normal HUVECs.

Moreover, in vivo, CA-5f (40 mg/kg, i.p., every 2 days for up to 30 days) potently inhibits the growth of tumor in nude mice bearing A549 lung cancer cells.

And that, CA-5f (40 mg/kg, i.p.) suppressed autophagic flux and induces apoptosis in nude mice bearing A549 lung cancer cells.

To conclude, due to its well toleration and potency, CA-5f is a promising clinical drug for NSCLC treratment.

Zhang L, et al. Identification of compound CA-5f as a novel late-stage autophagy inhibitor with potent anti-tumor effect against non-small cell lung cancer. Autophagy. 2019 Mar;15(3):391-406.