Bromelain inhibits nuclear factor kappa‐B translocation, driving human epidermoid carcinoma A431 and melanoma A375 cells through G₂/M arrest to apoptosis

Abstract

Bromelain, obtained from pineapple, is already in use clinically as adjunct in chemotherapy. Our objective was to test its ability to act as a sole anti-cancer agent. Therefore, we describe its anti-proliferative, anti-inflammatory and subsequent anti-cancer effects in vitro, against human epidermoid carcinoma-A431 and melanoma-A375 cells. Bromelain exhibited reduction in proliferation of both these cell-lines and suppressed their potential for anchorage-independent growth. Further, suppression of inflammatory signaling by bromelain was evident by inhibition of Akt regulated-nuclear factor-kappaB activation via suppression of inhibitory-kappaBα phosphorylation and concomitant reduction in cyclooxygenase-2. Since, the inflammatory cascade is well-known to be closely allied to cancer; we studied the effect of bromelain on events/molecules central to it. Bromelain caused depletion of intracellular glutathione and generation of reactive oxygen-species followed by mitochondrial membrane depolarization. This led to bromelain-induced cell-cycle arrest at G(2)/M phase which was mediated by modulation of cyclin B1, phospho-cdc25C, Plk1, phospho-cdc2, and myt1. This was subsequently followed by induction of apoptosis, indicated by membrane-blebbing, modulation of Bax-Bcl-2 ratio, Apaf-1, caspase-9, and caspase-3; chromatin-condensation, increase in caspase-activity and DNA-fragmentation. Bromelain afforded substantial anti-cancer potential in these settings; hence we suggest it as a potential prospect for anti-cancer agent besides only an additive in chemotherapy.

Bromelain: Methods of Extraction, Purification and Therapeutic Applications

“…Bromelain remarkably results in tumor regression for certain cell lines. These include P-388 leukemia, sarcoma (S-37), A-431 epidermoid carcinoma, A-375 melanoma, lewis lung cancer and ADC-755 breast cancer (Bhui et al 2011;Pavan et al 2012). Furthermore, the use of bromelain in conjugation with chemotherapeutic medicine improves the efficiency of these drugs to certain extent (Pillai et al 2013;Amini et al 2014).…”

Evaluation of Anti-Inflammatory Activity of Pseudananas macrodontes (Morr.) Harms (Bromeliaceae) Fruit Extract in Rats

“…All doses tested produced signifi cant inhibition after 7 h. It is known that indomethacin inhibits prostaglandins production (by inhibition of COX-1), while bromelain, in other experimental models, has been shown to reduce the production of NO (Wen et al, 2006) and prostaglandins (Bhui et al, 2011), as well as neutrophil migration (Fitzhugh et al, 2008). These results allow us to conclude that PPE Pm acts preferentially on the second rather than the fi rst phase of carrageenaninduced edema, which could be explained by a better bioavailability and/or increased specifi city against the release/action of mediators involved in the second phase (neutrophils, prostaglandins, and NO), whose production usually peaks between 3 and 6 h after injection of carrageenan (Salvemini et al, 1996).…”

“…The anti-infl ammatory activity of bromelain involves an increase in the fi brinolytic activity, enhancement of plasmin concentration by activation of the conversion of plasminogen to plasmin, decrease of the levels of plasma fi brinogen, bradykinin, and prekallikrein (Maurer, 2001), decrease of prostaglandin E 2 (PGE 2 ), thromboxane A 2 , and substance P levels (Vellini et al, 1986;Gaspani et al, 2002), as well as the modulation of cell surface molecules involved in migration (Fitzhugh et al, 2008) and cellular activation (Hale and Haynes, 1992;Mynott et al, 1999;Hale et al, 2002), and reduction of cyclooxygenase-2 (COX-2) expression by inhibing the activation of nuclear factor kappa-B (NF-KB) (Bhui et al, 2011). Even though the mechanism of the anti-infl ammatory action of bromelain has not yet been defi nitively elucidated, its proteolytic activity appears to be implicated (Fitzhugh et al, 2008;Hale and Haynes, 1992;Mynott et al, 1999;Hale et al, 2002Hale et al, , 2005.…”

Therapeutic Applications and Benefits from Postsurgical Use of the Phytotherapeutic Bromelain in Otorhinolaryngology: A Non- Interventional Study

“…The phytotherapeutic drug has been used since decades for the treatment of inflammatory diseases, injuries and postsurgical conditions [1][2][3]. The mode of action of bromelain has yet to be clarified in detail [4], even though various biological activities have been described that may contribute to or may be considered as, a consequence of the anti-inflammatory action, the reduction in pain and edema-protective, edema-reducing properties [5][6][7][8][9][10][11][12]. In particular due to its anti-edematous and pain-reducing properties, bromelain is used in order to enhance postoperative recovery and thereby may contribute to a decrease in the use of non-steroidal anti-inflammatory drugs (NSAIDs).…”