Activation of p53/p21/PUMA alliance and disruption of PI‐3/Akt in multimodal targeting of apoptotic signaling cascades in cervical cancer cells by a pentacyclic triterpenediol from Boswellia serrata

Abstract

Cervical carcinoma is a growing menace to women health worldwide. This study reports the apoptotic cell death in human cervical cancer HeLa and SiHa cells by a pentacyclic triterpenediol (TPD) from Boswellia serrata by a mechanism different from reported in HL-60 cells. It caused oxidative stress by early generation of nitric oxide and reactive oxygen species that robustly up regulated time-dependent expression of p53/p21/PUMA while conversely abrogating phosphatidylinositol-3-kinase (PI3K)/Akt pathways in parallel. TPD also decreased the expression of PI3K/pAkt, ERK1/2, NF-kappaB/Akt signaling cascades which coordinately contribute to cancer cell survival through these distinct pathways. The tumor suppressor p53 pathway predominantly activated by TPD further up-regulated PUMA, which concomitantly decreased the Bcl-2 level, caused mitochondrial membrane potential loss with attendant translocation of Bax and drp1 to mitochondria and release of pro-apoptotic factors such as cytochrome c and Smac/Diablo to cytosol leading to caspases-3 and -9 activation. In addition both the phospho-p53 and p21 were found to accumulate heavily in the nuclear fraction with attendant decrease in topoisomarase II and survivin levels. On the contrary, TPD did not affect the extrinsic signaling transduction pathway effectively through apical death receptors. Interestingly, N-acetyl cysteine, ascorbate and s-methylisothiourea (sMIT) rescued cells significantly from TPD induced DNA damage and caspases activation. TPD may thus find usefulness in managing and treating cervical cancer.

Pharmacological evidences for cytotoxic and antitumor properties of Boswellic acids from Boswellia serrata

“…It activated p53 tumor suppressor pathway, which further up-regulated PUMA leading to decreased Bcl-2 level and loss of mitochondrial membrane potential associated with Bax translocation, cytochrome-c release as well as activation of caspase-3 and caspase-9 (Bhushan et al, 2009). …”

Triterpenoid resinous metabolites from the genus Boswellia: pharmacological activities and potential species-identifying properties

“…Many studies have demonstrated the potent anti-neoplastic activities of triterpenoids acids obtained from frankincense, and especially boswellic acids (BAs) and their derivatives. These compounds have been shown to possess potential chemoprevention effects in prostate cancer [8,9], cervical cancer [10], breast cancer [11], colorectal cancer [12], pancreatic cancer [13] and bladder cancer [14]. In light of what is known of the medicinal properties of these metabolites, the present review places special emphasis on the pharmacological activities of the characteristic components of frankincense, such as acetyl- 11-keto-β-boswellic acid (AK-β-BA) (4).…”

Design and synthesis of a new class of cryptophycins based tubulin inhibitors

“…Cells were lysed with cold Cell lysis buffer (RIPA, Sigma with 50 mM NaF, 0.5 mM NaVO 4, 2 mM PMSF and 1% protease inhibitor cocktail) for 40 min. Cells were centrifuged at 12000 Â g for 15 min at 4 C and the supernatant was collected as whole cell lysates for western blot analysis [25].…”