Abstract
The potential of gossypol and of its R-(−)-enantiomer (R-(−)-gossypol acetic acid, AT-101), has been evaluated for treatment of cancer as an independent agent and in combination with standard chemo-radiation-therapies, respectively. This review assesses the evidence for safety and clinical effectiveness of oral gossypol/AT-101 in treating various types of cancer. The databases PubMed, MEDLINE, Cochrane, and ClinicalTrials.gov were examined. Phase I and II trials as well as single arm and randomized trials were included in this review. Results were screened to determine if they met inclusion criteria and then summarized using a narrative approach. A total of 17 trials involving 759 patients met the inclusion criteria. Overall, orally applied gossypol/AT-101 at low doses (30 mg daily or lower) was determined as well tolerable either as monotherapy or in combination with chemo-radiation. Adverse events should be strictly monitored and were successfully managed by dose-reduction or treating symptoms. There are four randomized trials, two performed in patients with advanced non-small cell lung cancer, one in subjects with head and neck cancer, and one in patients with metastatic castration-resistant prostate cancer. Thereby, standard chemotherapy (either docetaxel (two trials) or docetaxel plus cisplatin or docetaxel plus prednisone) was tested with and without AT-101. Within these trials, a potential benefit was observed in high-risk patients or in some patients with prolongation in progression-free survival or in overall survival. Strikingly, the most recent clinical trial combined low dose AT-101 with docetaxel, fluorouracil, and radiation, achieving complete responses in 11 of 13 patients with gastroesophageal carcinoma (median duration of 12 months) and a median progression-free survival of 52 months. The promising results shown in subsets of patients supports the need of further specification of AT-101 sensitive cancers as well as for the establishment of effective AT-101-based therapy. In addition, the lowest recommended dose of gossypol and its precise toxicity profile need to be confirmed in further studies. Randomized placebo-controlled trials should be performed to validate these data in large cohorts.
Highlights
Gossypol is a complex polyphenolic compound naturally occurring in the glands, leaves, stems, roots, and seeds of cotton plants with the highest concentration in the seeds [1,2]
Thereby, we systemically examine the available data about gossypol/AT-101 application within clinical investigations and focus on clinical outcomes, dose-limiting toxicities, and the relation of gossypol/AT-101 to potential cancer parameters as possible predictable markers of disease status or progression
To summarize the results of clinical trials in which cancer patients were treated with gossypol/AT-101, either as a single agent or in combination with standard therapies, a guideline defining the methods of search and analysis of the findings was developed
Summary
Gossypol is a complex polyphenolic compound naturally occurring in the glands, leaves, stems, roots, and seeds of cotton plants with the highest concentration in the seeds [1,2]. Gossypol is a strongly colored yellow, crystalline pigment, which is almost insoluble in water and hexane and, in contrast, soluble in acetone, chloroform, ether, and Pharmaceuticals 2022, 15, 144. Gossypol is a strongly colored yellow, crystalline pigment, which is almost insoluble in water and hexane and, in contrast, soluble in acetone, chloroform, ether, and methyl methyl ethyl ketone (butanone). It ispartially partially soluble in crude vegetable chemethyl ketone. 2,2 formula is C30H30O8 and the systematic name is 2,2′-bis (formyl-1,6,7-trihydroxy-5isopropanyl-3-methylnaphthalene) [2,3].
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