Bacterial proteins: A new class of cancer therapeutics

Abstract

Cancer is a complex disease with a network of multiple metabolic pathways that are interlinked to promote growth and resist immune surveillance.  Such a network is efficiently maintained through acquisition of multiple mutations in the human genome that result in the escape from normal cellular growth regulation and formation of lumps of  fast growing cells known as tumors.  The varied pathways through which cancer cells grow and inhibit their own cell death have made it difficult to develop effective drugs either to prevent the emergence of tumors or to check their rapid growth.  Current anticancer drugs are either small molecules or monoclonal antibodies that target and inhibit a key important step in cancer progression pathway, thereby significantly inhibiting their proliferation.  No effective drug or vaccine exists to prevent cancer initiation and drug resistance and toxicity are major problems in cancer chemotherapy.  This article describes recent attempts to develop bacterial proteins that are used as weapons by certain pathogenic bacteria with long term residence in human bodies to prevent invasion of their habitat by invaders such as cancers, viruses or parasites.  In one instance, such a protein, termed azurin, has been shown not only to have entry specificity in cancer cells and prevent cancer cell growth by interfering in multiple pathways by which cancer cells grow, but also to prevent induction of pre-cancerous lesion formation triggered by a potent carcinogen.  A 28 amino acid peptide derived from azurin, p28, also shows similar anticancer and cancer preventive activity.  In phase I human clinical trials, chemically-synthesized p28 has shown very little toxicity but significant beneficial effects, including partial and sometimes complete regression of metastatic refractory solid tumors in 15 advanced stage (stage IV) cancer patients where no conventional drugs were working.  A second such protein, termed ATP-01, very different from azurin and obtained from a different bacterium, has shown similar anticancer and anti-HIV/AIDS activity and a 30 amino acid peptide derived from it has anticancer activity similar to p28.  It would be of great interest to test these two proteins, should they prove to be non-toxic and non-immunogenic in humans, and the peptides derived from them, for their efficacy in cancer therapy and prevention.  Such efficacies can be tested, singly or in combination, in vulnerable people such as people with predisposition to cancer (women with BRCA1/2 mutations, for example) or in HIV/AIDS patients with Kaposi’s sarcoma or other forms of cancer.