| Description: |
Mahanine has effects on the activation of the apoptotic pathway in human leukemia U937 cells, causes the mitochondrial membranes to lose their permeability, resulting in caspase-3 activation and apoptosis. Mahanine can reverse an epigenetically silenced gene, RASSF1A in prostate cancer cells by inhibiting DNMT activity that in turn down-regulates a key cell cycle regulator, cyclin D1, is an encouraging therapeutic choice for advanced prostatic cancer. |
| Targets: |
JAK | Src | STAT | ROS | Chk | CDK | Akt | PI3K | p53 |
| In vitro: |
| Cancer Lett. 2014 Aug 28;351(1):81-90. | | Improved chemosensitivity in cervical cancer to cisplatin: synergistic activity of mahanine through STAT3 inhibition.[Pubmed: 24831030] | Toxicity reduction of cisplatin is necessary for improved treatment of cancer.
METHODS AND RESULTS:
Here we have demonstrated the synergistic growth-inhibitory effect of cisplatin on cervical cancer cells in-combination with a nontoxic herbal carbazole alkaloid, mahanine. Mahanine enhanced cisplatin-induced apoptosis and reduced its effective concentration ∼5-8 folds. Mahanine inhibited JAK1 and Src and subsequently promoted proteasome-mediated degradation of STAT3. This event was further enhanced in-combination with cisplatin and subsequently inhibited cancer cell migration.
CONCLUSIONS:
Collectively, our results revealed that mahanine may be a prospective agent to reduce the concentration of cisplatin in adjunct for the treatment of cancer and thereby decreasing its toxicity. | | Apoptosis. 2014 Jan;19(1):149-64. | | Mahanine synergistically enhances cytotoxicity of 5-fluorouracil through ROS-mediated activation of PTEN and p53/p73 in colon carcinoma.[Pubmed: 24052409] | 5-Fluorouracil (5-FU) alone or in combination with other drugs is the main basis of chemotherapeutic treatment in colorectal cancer although patients with microsatellite instability generally show resistance to 5-FU treatment.
METHODS AND RESULTS:
The present investigation is focussed on the mechanistic insight of a pure herbal carbazole alkaloid, Mahanine, as a single or in combination with 5-FU in colon cancer. We demonstrated that Mahanine-induced apoptosis involved reactive oxygen species (ROS)-mediated nuclear accumulation of PTEN and its interaction with p53/p73. Mahanine and 5-FU in combination exerted synergistic inhibitory effect on cell viability. This combination also enhanced ROS production, increased tumour suppressor proteins and suppressed chemo-migration.
CONCLUSIONS:
Taken together, our results revealed that Mahanine can be a potential chemotherapeutic agent with efficacy to reduce the concentration of toxic 5-FU in colon cancer. |
|
| In vivo: |
| Am J Cancer Res. 2014 Nov 19;4(6):629-47. | | Mahanine, a novel mitochondrial complex-III inhibitor induces G0/G1 arrest through redox alteration-mediated DNA damage response and regresses glioblastoma multiforme.[Pubmed: 25520856] | The Electron transport chain (ETC) is responsible for oxidative phosphorylation-mediated mitochondrial respiration.
METHODS AND RESULTS:
Here we wanted to address the Mahanine-induced targeted pathways in glioblastoma multiforme (GBM) in the context of G0/G1 phase arrest and redox alteration. We have demonstrated Mahanine, as a novel mitochondrial complex-III inhibitor which induced G0/G1 phase arrest in GBM. This event was preceded by accumulation of intracellular ROS by the inhibition of mitochondrial ETC. The accumulated ROS induced DNA damage response (DDR), that mediated Chk1/Chk2 upregulation and activation which were essential factors for the G0/G1 arrest. NAC-mediated scavenging of ROS generation reduced the propensity of G0/G1 phase arrest in GBM cells by Mahanine. Knockdown of Chk1/Chk2 also affected the cell cycle inhibitory potential of Mahanine. During G0/G1 arrest, other hallmark proteins like, cyclin D1/cyclin D3, CDK4/CDK6 and CDC25A were also downregulated. The G0/G1 phase restriction property of Mahanine was also established in in vivo mice model. Mahanine-induced complex-III inhibition triggered enhanced ROS in hypoxia responsible for higher G0/G1 arrest. Furthermore, we demonstrated that Mahanine-treated G0/G1 arrested cells were less potent to form xenograft tumor in vivo. Additionally, they exhibited reduced ability to migrate and form intracellular tube-like structures. Moreover, they became susceptible to differentiate and astrocyte-like cells were generated from the epithelial lineage.
CONCLUSIONS:
Taken together, our results established that complex-III of ETC is one of the possible potential targets of Mahanine. This nontoxic chemotherapeutic molecule enhanced ROS production, induced cell cycle arrest and thereafter regressed GBM without effecting normal astrocytes. |
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