Altholactone induces reactive oxygen species-mediated apoptosis in bladder cancer T24 cells through mitochondrial dysfunction, MAPK-p38 activation and Akt suppression

Abstract

Human bladder cancer is an aggressive tumor which frequently resists chemotherapy. Therefore, the search for new therapeutic agents is of great importance. Altholactone, isolated from Goniothalamus sp., has been reported to inhibit the growth of various types of cancer cells. However, no prior research has been conducted to demonstrate the antiproliferative potential of altholactone on bladder cancer. In the present study, we characterized the effect of altholactone on cell growth and apoptosis in bladder cancer T24 cells. Treatment with altholactone resulted in a significant reduction in cell viability, induction of apoptosis and generation of reactive oxygen species (ROS) in T24 cells. Furthermore, our results revealed that altholactone-induced apoptosis was associated with decreased expression of Akt phosphorylation and activation of MAPK‑p38. Altholactone treatment was also found to result in a significant loss of mitochondrial membrane potential, Bcl-2 downregulation and caspase-3 activation. Pretreatment of T24 cells with the antioxidant N-acetylcysteine (NAC) significantly inhibited activation of caspase-3 and MAPK-p38 and prevented inactivation of Akt and Bcl-2. Taken together, our data demonstrate that altholactone induces ROS-dependent apoptosis in T24 cells via a novel mechanism involving inhibition of Akt and provide the rationale for further in vivo and preclinical investigation of altholactone against bladder cancer.

Heat shock protein 27 downstream of P38-PI3K/Akt signaling antagonizes melatonin-induced apoptosis of SGC-7901 gastric cancer cells

“…Several reports have demonstrated that HSP27 can form multicomponent complexes with Akt, and P38, and this complex has been shown to be involved in controlling HSP27 phosphorylation and stress-induced apoptosis [ 17 , 27 , 28 ]. As reported previously, activation of P38 was accompanied by Akt suppression in the apoptotic process in some types of cancer cells [ 29 , 30 ]. Conversely, there also has a good evidence suggesting a link from MEKK4 and P38, via HSP27, to Akt activation, which is essential for the regulation of cell fate in response to apoptotic stress in human prostate cancer cells [ 31 ].…”

DecreasedTRPM7inhibits activities and induces apoptosis of bladder cancer cells via ERK1/2 pathway

“…Importantly, aberrant regulation of MAPK could contribute to cancer and other human diseases, including bladder cancer [6, 7]. Many studies have suggested that intracellular or extracellular calcium disorders might induce abnormal activation or deactivation of MAPK cascades [8, 9] and consequently initiate cancer development [10].…”

Gecko proteins induce the apoptosis of bladder cancer 5637 cells by inhibiting Akt and activating the intrinsic caspase cascade

“…1 B), suggesting that the effect of GPE on apoptosis was specific to cancer cells (8 , 11 , 22 , 23) . Considering the critical role of Akt pathway in the progression of bladder cancer (14 , 15 , 26) , with no corresponding cytotoxic effect on normal cells, our findings suggest that GPE can be a promising therapeutic candidate for the development of an anti-cancer drug for bladder cancer.…”

“…Akt is the typical survival factor in various cancer cells, including bladder cancer (13 - 15) , and Akt suppression was critical for exhibiting the anti-tumor effect of various bioactive peptides (14 , 16) . In addition, we had previously shown GPE induced cervical cancer cell death by inhibiting the Akt pathway (11) .…”