Involvement of Akt in mitomycin C and its analog triggered cytotoxicity in MCF‐7 and K562 cancer cells

Abstract

Mitomycin C (MC) is a well-known DNA alkylating agent. MC analog, 10-decarbamoyl mitomycin C (DMC), unlike MC, has stronger effects on cancer with p53 mutation. We previously demonstrated that MC/DMC could activate p21 in MCF-7 (p53-proficient) and K562 (p53-deficient) cells in a p53-independent mode. This study aimed to elucidate the upstream signaling pathway of p21 activation triggered by MC/DMC. Besides p53, Akt plays an important role on deactivating p21 . The results showed that MC/DMC inhibited Akt in MCF-7 cells, but not in K562 cells. By knocking down p53, the Akt inhibition in MCF-7 cells was alleviated. This implied that the deactivated Akt caused by MC/DMC was p53-dependent. With Akt activator (SC79), p21 activation triggered by MC/DMC in MCF-7 cells was not reduced. This indicated that Akt inhibition triggered by MC/DMC was not associated with MC/DMC-induced p21 activation. Label-free quantitative proteomic profiling analysis revealed that DMC has a stronger effect on down-regulating thePI3K/Akt signaling pathway in MCF-7 cells as compared to MC. No significant effect of MC/DMC on PI3K/Akt in K562 cells was observed. In summary, MC/DMC regulate Akt activation in a p53-dependent manner. This Akt deactivation is not associated with p21 activation in response to MC/DMC.

Synthesis of Oligonucleotides containing the cis‐Interstrand Crosslink Produced by Mitomycins in their Reaction with DNA

“…Importantly, the S stereochemical configuration (cis ) at C1“ of the ICL produced by DMC correlates with the higher toxicity of DMC in human cancer cells compared to MC . In this manuscript, from now on, we will refer to dG adducts and ICLs with a R stereochemistry at C1′′as α‐adducts ( trans ), while adducts with a C1′′‐ S configuration will be denoted as β‐adducts ( cis ).…”

History, presence, and future of mitomycin C in glaucoma filtration surgery

“…Second, it has been noted that MMC activation is also nicotinamide adenine dinucleotide phosphate (NADPH)-dependent [29]. Third, it is known that MMC activates the PI3K/ Akt signaling pathway in a p53-dependant manner [27,32]. Activation of MMC will result in alkylation/ crosslinking of DNA as shown in Fig.…”

“…MMC is not only known as an alkylating agent [24,32], but also as an antibiotic [34], cross-linking reagent [35], and a nucleic acid synthesis inhibitor [36]. In addition to the specific inhibition of DNA synthesis due to alkylation, inhibition of RNA and protein synthesis seem to be nonspecific manifestations of MMC cell toxicity [26,29].…”

“…MMC can function in GFS due to the alkylating effect of the drug [24,26,32]. Thereby, it inhibits cell proliferation/differentiation (e.g.…”

Synthesis of Oligonucleotides Containing Trans Mitomycin C DNA Adducts at N6 of Adenine and N2 of Guanine

“…Such compounds provide substrates to study DNA damage signaling, sensing or repair mechanisms. [12][13][14][15][16][17][18] In the case of MC, synthetic routes have been developed to access modified oligonucleotides containing dG monoadducts 1 a, [19] 2 b, [20][21][22] 5 [23] and 6 [24] as well as ICLs 3 a [25] and 3 b [22] at a single position of their base sequences (Figure 1). Typically, the syntheses involve the reaction between a chemically reduced mitomycin and a duplex oligonucleotide.…”