Mitochondria as target to inhibit proliferation and induce apoptosis of cancer cells: the effects of doxycycline and gemcitabine

Abstract

Doxycycline has anti-tumour effects in a range of tumour systems. The aims of this study were to define the role mitochondria play in this process and examine the potential of doxycycline in combination with gemcitabine. We studied the adenocarcinoma cell line A549, its mitochondrial DNA-less derivative A549 ρ° and cultured fibroblasts. Treatment with doxycycline for 5 days resulted in a decrease of mitochondrial-encoded proteins, respiration and membrane potential, and an increase of reactive oxygen species in A549 cells and fibroblasts, but fibroblasts were less affected. Doxycycline slowed proliferation of A549 cells by 35%. Cellular ATP levels did not change. Doxycycline alone had no effect on apoptosis; however, in combination with gemcitabine given during the last 2 days of treatment, doxycycline increased caspase 9 and 3/7 activities, resulting in a further decrease of surviving A549 cells by 59% and of fibroblasts by 24% compared to gemcitabine treatment alone. A549 ρ° cells were not affected by doxycycline. Key effects of doxycycline observed in A549 cells, such as the decrease of mitochondrial-encoded proteins and surviving cells were also seen in the cancer cell lines COLO357 and HT29. Our results suggest that doxycycline suppresses cancer cell proliferation and primes cells for apoptosis by gemcitabine.

Targeting Mitochondria in Melanoma

“…Inhibition of mitochondrial protein synthesis leads to reduced mitochondrial respiration and ATP production in mammalian cells, ultimately resulting in growth inhibition. Rapidly dividing cancer cells with high energy demands are more sensitive to antibiotics compared with non-cancerous cells, as confirmed in many in vitro and in vivo studies [ 31 , 38 ]. Similarly, in our study, HDFs, as non-cancerous skin cells, were less sensitive to antibiotics compared to melanoma cells.…”

“…The endosymbiotic hypothesis proposes that mitochondria originated from bacteria [ 63 ]. Therefore, some antibiotics such as those used in the present study (TIG, DOX and AZI) reduce mitochondrial and bacterial translation by binding to their ribosomes [ 31 , 38 , 64 ]. Inhibition of mitochondrial protein synthesis leads to reduced mitochondrial respiration and ATP production in mammalian cells, ultimately resulting in growth inhibition.…”

“…A growing number of pre-clinical and clinical studies indicates that antibiotics like tigecycline (TIG), doxycycline (DOX) and azithromycin (AZI) as well as the anti-parasitic drug pyrvinium pamoate (PP) have the potential to inhibit the growth of a wide spectrum of solid tumors and blood cancers. These drugs impact mitochondrial functions, for example by reducing mitochondrial biogenesis, altering mitochondrial morphology, lowering OXPHOS activity and increasing the level of reactive oxygen species [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. In vitro analysis showed that cancer cells depleted of mitochondrial DNA develop resistance to these types of antimicrobial drugs, indicating that mitochondria are specific targets of such treatments [ 31 ].…”

Reverse transcriptase inhibition potentiates target therapy in BRAF-mutant melanomas: effects on cell proliferation, apoptosis, DNA-damage, ROS induction and mitochondrial membrane depolarization

“…Of note the same ndings were observed also in A375 cells (Additional le 4: Figure S4). Hereafter, we assess whether the depolarization of mitochondrial inner transmembrane potential as a marker of apoptosis (38,39) may occur in different combinatorial regimens. Data indicate that this was indeed the case.…”

Targeting the Mitochondrial Metabolic Network: A Promising Strategy in Cancer Treatment

“…Among the FDA-approved antibiotics that show the greatest potential in targeting mitochondrial cancer function are tigecycline and doxycycline. These molecules have been proven to reduce mitochondrial function and tumor stemness in many cancer models, both in vitro and in vivo [ 148 , 149 , 150 , 151 , 152 , 153 , 154 ]. In particular, in a clinical pilot study, doxycycline was shown to effectively reduce cancer stem cells in early breast cancer patients [ 155 ].…”