A Novel Mithramycin Analogue with High Antitumor Activity and Less Toxicity Generated by Combinatorial Biosynthesis

Abstract

Mithramycin is an antitumor compound produced by Streptomyces argillaceus that has been used for the treatment of several types of tumors and hypercalcaemia processes. However, its use in humans has been limited because its side effects. Using combinatorial biosynthesis approaches, we have generated seven new mithramycin derivatives, which either differ from the parental compound in the sugar profile or in both the sugar profile and the 3-side chain. From these studies three novel derivatives were identified, demycarosyl-3D-β-d-digitoxosyl-mithramycin SK, demycarosyl-mithramycin SDK and demycarosyl-3D-β-d-digitoxosyl-mithramycin SDK, which show high antitumor activity. The first one, which combines two structural features previously found to improve pharmacological behavior, was generated following two different strategies, and it showed less toxicity than mithramycin. Preliminary in vivo evaluation of its antitumor activity through hollow fiber assays, and in subcutaneous colon and melanoma cancers xenografts models, suggests that demycarosyl-3D-β-d-digitoxosyl-mithramycin SK could be a promising antitumor agent, worthy of further investigation.

Sp1 transcription factor: A long-standing target in cancer chemotherapy

“…Many of the drugs and natural molecules reviewed here can be considered safe enough (D'Incalci, et al, 2007;Minotti, et al, 2004;Núñez, et al, 2012;Sankpal, et al, 2013), which would support or accelerate their clinical usage. However, experimental data should be handled with care in translational medicine based on inhibiting Sp transcription factors, given that Sp1 and/or Sp3 can cooperatively activate several genes through the interaction with other transcription factors or their DNA-binding sites Vizcaíno, et al, 2012;Wierstra, 2008).…”

Genome-Wide Modulation of Gene Transcription in Ovarian Carcinoma Cells by a New Mithramycin Analogue

“…DIG-MSK shows in vivo and in vitro antitumor activities similar to other novel analogues like the structurally related MSK, but DIG-MSK is 10-fold less toxic in vivo than MTA and 25% less toxic than MSK [25]. Remarkably, the single maximum tolerated dose of DIG-MSK in mice is the highest among the mithramycin analogues [25]. DIG-MSK inhibits the growth of HCT-116 human colon carcinoma cells, where it inhibits the interaction between transcription factors and DNA [29].…”

“…New mithramycin analogues bearing both lower toxicity and higher biological activity are now available, providing new possibilities for therapeutic application [18], [19], [25]. MTA and its analogues tested to date can inhibit transcription both in vivo and in vitro by interfering with protein-DNA interactions, especially the inhibition of Sp1-dependent transcription [17], [18], [27]–[29].…”

Quantitative determination of mithramycin in human plasma by a novel, sensitive ultra-HPLC–MS/MS method for clinical pharmacokinetic application

“…Mithramycin has been used clinically against testicular cancer [2] and leukemia [3], and preclinical studies have shown activity against glioma [4], pancreatic cancer [5], prostate cancer [6], oral squamous cell carcinoma [7], and lung and esophageal cancer [8]. Patients receiving mithramycin often develop hepatotoxicity [9]; various analogs have been developed in an attempt to curtail dose-limiting side effects [10–12]. …”