Vorinostat CAS 149647-78-9

CTCL is a type of lymphoma that begins as a lesion in the skin and then spreads to the lymphatic system or other organs. The cause of CTCL is currently unclear, and it may be related to chronic and long-term exposure to chemicals in the environment, such as “pesticides”. Epidemiology shows that the disease mostly occurs in adults aged 40 to 60, with a male-to-female ratio of about 2:1, and the attack rate increases with age.

There are 2 main phenotypes of CTCL: one is erythroderma and the other is mycosis fungoides. Vorinostat can treat CTCL by inducing cell differentiation, blocking cell cycle, and inducing cell regulation. Vorinostat has been approved by the US FDA in 2006 for the treatment of CTCL that has exacerbated, persisted, and relapsed or has not responded to 2 systemic agents. Anderson Cancer Center conducted a Phase II clinical study on vorinostat, mainly to observe the efficacy, safety and tolerability of vorinostat in patients with refractory CTCL.

Patients over 18 years old who were refractory or resistant to conventional chemotherapy and expected to survive for more than 3 months were divided into three groups. Group 1 was given vorinostat 400 mg· d – 1, the intermittent period was changed to 300 mg/d, and the average treatment time was 12 weeks; the patients in the second group were given 300 mg/time – 1, bid, 3 days a week, and the average treatment time was 7 weeks; the patients in the third group were given 300 mg/d mg/time, bid, the average treatment time is 7 weeks.

After the study, the effective rate of each group was observed. The effective rate of the first group was 31%, that of the second group was 9.1%, and that of the third group was 33.3%. The effective rates of the first group and the third group were significantly higher than those of the second group . Seven of 33 patients received vorinostat for 23 weeks or longer, including 4 in group 1, 1 in group 2, and 2 in group 3. In terms of pruritus symptom relief, 73% in group 1 were relieved, compared with 18% in group 2 and 44% in group 3.

In terms of safety and adverse reactions, the most common adverse reactions included fatigue (78%), diarrhea (60%), nausea (60%), thrombocytopenia (54%), taste disturbance (51%), dry mouth (38%) % ), although there was no significant difference in the incidence of adverse reactions among the 3 groups, 41.7% of patients in group 3 experienced grade 3-4 thrombocytopenia, while only 7.7% and 8.3% of patients in groups 1 and 3 Grade 3-4 thrombocytopenia.

In the laboratory study of the combination of HDAC inhibitor vorinostat and PARP inhibitor PJ34 on leukemia cells, they were divided into 3 groups, namely vorinostat group, PJ34 group and two-drug combination group. Into HL60, MOLT4, U937, K562 cell culture medium for culture, evaluate cell proliferation, apoptosis, mitochondrial membrane potential and cell cycle. The results showed that the PJ34 group had no effect on cell growth, while the vorinostat group decreased cell proliferation, decreased mitochondrial membrane potential, and increased the percentage of apoptotic cells.

The combination of the two drugs can further reduce the proliferation of HL60, MOLT4 and K562 cells, increase their apoptosis, and weaken the mitochondrial membrane potential, but has no effect on U937 cells. This result shows that vorinostat can inhibit the proliferation of myeloid leukemia strains in vitro.

Studies have found that vorinostat and carfilzomib have synergistic effects on T-lymphoblastic leukemia cells. Carfilzomib is a proteasome inhibitor and vorinostat is a histone deacetylase inhibitor. In this study, lethal concentrations of carfilzomib and low concentrations of vorinostat acted on T lymphocyte leukemia cells exposed to carbon monoxide, and the leukemia cells underwent apoptosis, reactive oxygen species (ROS) increased sharply, and mitochondrial membrane potential ( MMP) was significantly reduced, cytochrome c release was increased, caspase-9 and -3 activation was enhanced, and PARP kinase cleavage. Furthermore, the combination blocked the G2-M phase of leukemia cells. These results indicate that carfilzomib and vorinostat have a clear synergistic effect on T-lymphoblastic leukemia cell lines.

Multiple myeloma, the most common type of malignant plasma cell disease, is characterized by the malignant proliferation of monoclonal plasma cells and the secretion of large amounts of monoclonal immunoglobulin. The role of vorinostat as a sirtuin inhibitor in the treatment of multiple relapsed multiple myeloma has gradually attracted attention in recent years. Vorinostat combined with bortezomib in the treatment of multiple myeloma can prolong the median survival of patients. Enrollment was non-refractory multiple myeloma patients with ECOG score ≤2 who had progressed on previous treatment.

Vorinostat, an HDAC inhibitor, sensitizes breast cancer cells to taxanes and mAbs by inhibiting HDAC6 and Hsp90 pathological proteins.