Cephalostatin 1 Analogues: Promising Anti-Tumor Drugs
Cancer is a leading cause of death worldwide, and the number of deaths is projected to continuously rise in the coming years. Surgery, chemotherapy, and radiotherapy are the most common treatment options for different types of cancer. They can be used singularly or in combination with other treatments.
However, there are substantial variations in response to treatment. These variations indicate that intrinsic or acquired therapeutic resistance exists in cancer patients, which leads to treatment failures, disease progression, and mortality.
Understanding cancer at the molecular level led to the development of novel targeted therapeutic agents and methods to reduce the diverse heterogeneity among tumors and the traditional cytotoxic chemotherapy. Nowadays, there are great efforts focusing on maximizing chemotherapy treatment efficiency, minimizing the side effects resulting from it, understanding the molecular mechanisms responsible for drug resistance, and identifying new drugs which might overcome drug resistance.
Cells are the basic structural and functional unit in all living organisms and must be maintained under strict control. Specific factors contribute to the disruption of normal cell functions, ultimately leading to the development of abnormal cancer cell. Cancer is an abnormal growth of cells that is caused by multiple changes in gene expression leading to deregulation between cell proliferation and cell death, which leads to the development of a population of cells that can invade tissue and metastasize to distant organs (metastasis).
Cancer is the second-leading cause of death in developing countries and is the main cause of death in developed countries. This makes cancer treatment a priority worldwide. Surgery, radiation, and cytotoxic chemotherapy are the conventional methods of cancer treatment. Chemotherapy exhibits its anticancer effect by inducing apoptosis (programmed cell death) in cancer cells. However, chemoresistance limits chemotherapy efficacy since the population of tumor cells will overcome the treatment, leading to a recurrence of the tumor.
Cephalostatin1, a potent anti-cancer agent, is a natural bis-steroidal alkaloid extracted from a tiny marine worm called Cephalodiscus gilchristi found in the Indian ocean of Southeast Africa. Cephalostatin1 affects cancer cells in the subnanomolar to picomolar ranges, making it one of the most powerful cancer therapies. In addition, it induces apoptosis in an atypical method which gives it the ability to overcome chemoresistance.
Although cephalostatin 1 is highly effective anticancer compound, there are limitations that reduce its utilization. The marine worm that produces cephalostatin 1 lives several meters deep in water inhabited by white sharks, which mandates the need for professional divers to reach that depth. In addition, the divers have to collect the worm under the danger of white sharks, which makes the collection of the worm laborious and dangerous. In addition, to obtain 139 mg of cephalostatin 1, 166 kg wet mass of the marine worm is needed, making the yield too low to make it cost-effective.
Due to cephalostatin 1’s unusual structure, the attempts of organic chemists to synthesize this drug requires around 70 complicated steps with very low yield. The combination of the collection difficulties and the synthesis complications led scientists to synthesize cephalostatin 1-related compounds (analogues; CAs) looking for utilizable alternatives of cephalostatin 1.
Cephalostatin 1 analogues
Combination of the collection difficulties and the synthesis complications and since cephalostatin 1 has an exceptional anti-proliferative activity led to a particular interest in the synthesis of cephalostatin 1 analogues. Some of these cephalostatin 1 analogues were found to be biologically active and some were not.
Our group was successful in synthesizing a panel of cephalostatin 1 analogues; two of these analogues were tested to evaluate their cytotoxicity against cancer and normal cells. Our results indicated that both CAs induced apoptosis in six different cancer lines. However, neither analogue at 10 μM (the highest concentration tested) killed more than 14% of any of three types of normal human cells suggesting their cytotoxicity is cancer-specific.
In addition, CA’s treatment was able to induce inhibition of clonal tumor growth, which indicates that these cephalostatin analogues could be used to circumvent chemoresistance. Moreover, we found that the two CA’s induce cell death through atypical apoptosis indicating the potential usability of these analogues in cancer treatment.
Currently, we are testing additional cephalostatin 1 analogues looking for utilizable drugs which can overcome chemoresistance. In addition, we are studying the anti-tumor activities (efficacy, toxicity, and pharmacokinetics) of the two CAs in an animal model. Because of their ease of synthesis and potent anti-proliferative activities, these cephalostatin analogues represent promising anticancer drugs. In conclusion, there is still a need for developing effective anticancer drugs with new mechanisms of action.
These findings are described in the article entitled Cephalostatin 1 analogues activate apoptosis via the endoplasmic reticulum stress signaling pathway, recently published in the European Journal of Pharmacology. This work was conducted by Lubna H. Tahtamouni, Zainab A. Al-Mazaydeh, Rema A. Al-Khateeb, Reem N. Abdellatif, and Salem R. Yasin from The Hashemite University, Mansour M. Nawasreh from the Al-Balqa Applied University, Randa M. Bawadi from The University of Jordan, and James R. Bamburg from Colorado State University.