Chloramphenicol Causes Mitochondrial Stress, Decreases ATP Biosynthesis, Induces Matrix Metalloproteinase-13 Expression, and Solid-Tumor Cell Invasion

Abstract

Overuse and abuse of antibiotics can increase the risk of cancer. Chloramphenicol can inhibit both bacterial and mitochondrial protein synthesis, causing mitochondrial stress and decreased ATP biosynthesis. Chloramphenicol can accelerate cancer progression; however, the underlying mechanisms of chloramphenicol in carcinogenesis and cancer progression are still unclear. We found that chloramphenicol can induce matrix metalloproteinase (MMP)-13 expression and increase MMP-13 protein in conditioned medium, resulting in an increase in cancer cell invasion. Chloramphenicol also activated c-Jun N-terminal kinases (JNK) and phosphatidylinositol 3-kinase (PI-3K)/Akt signaling, leading to c-Jun protein phosphorylation. The activated c-Jun protein has been proven to activate binding to the MMP-13 promoter and also upregulate the amount of MMP-13. Both the SP 600125 (JNK inhibitor) and LY 294002 (PI-3K/Akt inhibitor) can inhibit chloramphenicol-induced c-Jun phosphorylation, MMP-13 expression, and cell invasion. Overexpression of the dominant-negative JNK and PI-3K p85 subunit also negate chloramphenicol-induced responses. Other antibiotics that cause mitochondrial stress and a decrease in ATP biosynthesis also induce MMP-13 expression. These findings suggest that chloramphenicol-induced PI-3K/Akt, JNK phosphorylation, and activator protein 1 activation might function as a novel mitochondrial stress signal that result in an increase of MMP-13 expression and MMP-13-associated cancer cell invasion. The findings of this study confirms that chloramphenicol, and other 70S ribosomal inhibitors, should be administered with caution, especially during cancer therapy.

The antibiotic chloramphenicol may be an effective new agent for inhibiting the growth of multiple myeloma

“…Our experiments confirmed that lower concentrations of chloramphenicol (25 μg/mL) significantly inhibit primary MM cell proliferation, which is consistent with a previous report of inhibition of mouse myeloma cell proliferation by chloramphenicol [31]. Because chloramphenicol is highly fat soluble [11], it likely reaches higher concentrations in the bone marrow, where MM cells mainly survive and accumulate, than in the serum [32]. Thus, higher local drug concentrations may inhibit the growth of MM cells.…”

“…This inhibition of energy metabolism would change tumor biology, making it unconducive to tumor cell growth [8]. In contrast to previous reports [10, 11], a small increase in the chloramphenicol dose (to ≥ 50 μg/mL) greatly suppressed tumor growth while further decreasing ATP levels. These phenomena suggest that a deep deficiency in ATP can effectively suppress tumor cell proliferation.…”

“…Chloramphenicol is highly lipid soluble [11, 30]. Its target serum concentration for treating infectious diseases is 10–30 μg/mL in serum, which corresponds to a dose of 50–100 mg/kg/day [19].…”

Emancipating Chlamydia: Advances in the Genetic Manipulation of a Recalcitrant Intracellular Pathogen

“…Exogenous drug resistance cassettes conferring chloramphenicol (cat), ␤-lactam (bla), and blasticidin (Shble) resistance are currently used as markers to select transformed Chlamydia (18,19,27,28). However, the bla cassette cannot be used in urogenital strains; chloramphenicol can cause mitochondrial stress (54), limiting its use during continuous passaging; and blasticidin S exhibits antibiotic activity toward both prokaryotic and eukaryotic cells and thus can be toxic to host cells. In addition, not all Chlamydiae species are susceptible to these antibiotics, such as Parachlamydia acanthamoeba, which is naturally resistant to ␤-lactams (55).…”

Antibiotics May Trigger Mitochondrial Dysfunction Inducing Psychiatric Disorders

“…Abuse of chloramphenicol stimulates tumor development. This drug works through the JNK and PI3k pathways, which lead to a phosphorylated c-Jun protein binding to the promoter region of the matrix metalloproteinase-13 region (MM-13) [65]. The increased levels of the MM-13 protein lead to tumor development [66].…”