Homoharringtonine (HHT) is a chemical compound derived from natural sources, developed into a medication used in oncology. It treats certain cancers by interfering with cellular processes. Its development highlights advancements in drug discovery. HHT is recognized for its distinct mechanism of action, offering a different approach compared to other cancer treatments.
Origin and Development
Homoharringtonine is an alkaloid identified from Cephalotaxus plants (plum-yew trees) native to East Asia, specifically Cephalotaxus fortunei and Cephalotaxus harringtonia. Researchers described HHT in the 1970s, leading to Chinese investigators exploring its potential as an anticancer agent.
Challenges in consistent production, supply, and toxicity of early formulations hindered its widespread use. A semi-synthetic form, omacetaxine mepesuccinate (Synribo), was developed to overcome these issues. It received U.S. Food and Drug Administration (FDA) approval in 2012.
Medical Applications in Leukemia Treatment
HHT’s primary medical application is in treating Chronic Myeloid Leukemia (CML). This specific type of cancer involves the abnormal growth of white blood cells in the bone marrow and blood. HHT is prescribed for adult CML patients who have developed resistance to or cannot tolerate other standard treatments.
It is relevant for patients who have not responded to tyrosine kinase inhibitors (TKIs), a class of drugs used to treat CML. A notable example of resistance that HHT can help overcome is the T315I mutation in the BCR-ABL gene, which makes CML cells highly resistant to several TKIs. Clinical trials have investigated HHT’s efficacy in CML, including in patients with T315I mutations, often administered in induction and maintenance phases.
Mechanism of Action
Homoharringtonine functions as a protein synthesis inhibitor. It prevents cancer cells from producing new proteins required for survival and multiplication. HHT interacts with ribosomes within cancer cells, the cellular machinery responsible for protein production. It binds to the A-site cleft of the ribosome, thereby inhibiting the initial elongation step of protein translation.
This mechanism leads to rapid inhibition of protein synthesis, particularly affecting proteins with short half-lives that need constant replenishment. Examples of such proteins include myeloid cell leukemia 1 (Mcl-1), cyclin D1, and c-Myc, which are often overexpressed in leukemic cells and play roles in cell proliferation and survival. Tyrosine kinase inhibitors (TKIs) target specific enzymes involved in cancer cell signaling. HHT’s distinct approach of broadly inhibiting protein synthesis provides an alternative strategy that can be effective even when cancer cells develop mutations that render TKIs ineffective, such as the T315I mutation.
Administration and Side Effects
Homoharringtonine, in its semi-synthetic form omacetaxine mepesuccinate, is administered through subcutaneous injection. Treatment often involves specific cycles, such as twice daily injections for 14 consecutive days during an induction phase, followed by maintenance therapy with injections for 7 consecutive days every 28 days. The exact dosing schedule can vary based on the patient’s response and disease phase.
Patients undergoing treatment with HHT may experience side effects. A common effect is myelosuppression, which is a reduction in the production of blood cells by the bone marrow. This can lead to low counts of various blood components, including thrombocytopenia (low platelets), neutropenia (low white blood cells), and anemia (low red blood cells). Myelosuppression can increase the risk of infections and bleeding.
Other common effects reported include fatigue, nausea, vomiting, and diarrhea. Reactions at the injection site are possible. Healthcare providers closely monitor blood counts and other symptoms to manage these effects during treatment.