Paclitaxel resistance development is associated with biphasic changes in reactive oxygen species, mitochondrial membrane potential and autophagy with elevated energy production capacity in lung cancer cells: A chronological study

Abstract

Paclitaxel (Tx) is one of the first-line chemotherapeutic drugs used against lung cancer, but acquired resistance to this drug is a major challenge against successful chemotherapy. In this work, we have focused on the chronological changes of various cellular parameters and associated effect on Tx (10 nM) resistance development in A549 cell line. It was observed, at initial stage, the cell death percentage due to drug treatment had increased up to 20 days, and thereafter, it started declining and became completely resistant by 40 days. Expressions of βIII tubulin and drug efflux pumps also increased over the period of resistance development. Changes in cellular autophagy and reactive oxygen species generation showed a biphasic pattern and increased gradually over the course of upto 20 days, thereafter declined gradually; however, their levels remained higher than untreated cells when resistance was acquired. Increase in extracellular acidification rates and oxygen consumption rates was found to be directly correlated with acquisition of resistance. The depolarisation of mitochondrial membrane potential was also biphasic; first, it increased with increase of cell death up to 20 days, thereafter, it gradually decreased to normal level along with resistance development. Increase in activity of catalase, glutathione peroxidase and glutathione content over these periods may attribute in bringing down the reactive oxygen species levels and normalisation of mitochondrial membrane potential in spite of comparatively higher reactive oxygen species production by the Tx-resistant cells.

Overcoming resistance to mitochondrial apoptosis by BZML‐induced mitotic catastrophe is enhanced by inhibition of autophagy in A549/Taxol cells

“…Currently, Taxol is widely used in the treatment of NSCLC in the clinics. However, many patients have acquired resistance to Taxol, and even those who initially respond will eventually exhibit MDR . We have confirmed that BZML has potent anti‐cancer activity against Taxol‐sensitive or Taxol‐resistant A549 cells through different death modes in vitro .…”

“…However, many patients have acquired resistance to Taxol, and even those who initially respond will eventually exhibit MDR. [44][45][46][47] We have confirmed that BZML has potent anti-cancer activity against Taxol-sensitive or Taxol-resistant A549 cells through different death modes in vitro. 10 This paper aimed to evaluate the anticancer activity of BZML in vivo and the mechanism underlying the apoptosis resistance in BZML-treated A549/Taxol cells.…”

Essential roles of mitochondrial and heme function in lung cancer bioenergetics and tumorigenesis

“…Inhibition of mitochondrial complex I abolished the ability of the resistant cells to invade [ 8 ], suggesting the pivotal role of mitochondria in metastasis of resistant cells. Another recent study showed that mitochondrial oxygen consumption is a vital source of energy in paclitaxel-resistant lung adenocarcinoma cells [ 94 ]. In lung adenocarcinoma cell line A549, mitochondrial membrane depolarization increased during the initial phase where cells died in response to paclitaxel.…”

“…However, as the cells gained resistance, normal mitochondrial membrane are restored by increased activity of catalase and glutathione peroxidase which counteracted the effect of increased ROS produced as result of paclitaxel treatment. Further, paclitaxel-resistant cells exhibited elevated extracellular acidification rates and oxygen consumption [ 94 ]. Several studies have shown that many cancer cells which are resistant, rely on mitochondrial oxidative phosphorylation for energy [ 96 – 98 ].…”

“…Hence, targeting mitochondria could be an effective strategy to suppress drug-resistant cancer cells. Recent studies showed that targeted drug therapies, such as MAPK inhibitors, and first-line chemotherapeutic agents, such as platinum-based drugs, increase mitochondrial activity and OXPHOS [ 94 , 105 ]. These studies showed that a combination of first-line therapeutic agents and mitochondrial targeting agents would plausibly serve as an effective strategy to curtail tumor progression.…”