Anticancer properties and enhancement of therapeutic potential of cisplatin by leaf extract of Zanthoxylum armatum DC.
BACKGROUND
Clinical use of chemotherapeutic drug, cisplatin is limited by its toxicity and drug resistance. Therefore, efforts continue for the discovery of novel combination therapies with cisplatin, to increase efficacy and reduce its toxicity. Here, we screened 16 medicinal plant extracts from Northeast part of India and found that leaf extract of Zanthoxylum armatum DC. (ZALE) induced cytotoxicity as well as an effect on the increasing of the efficiency of chemotherapeutic drugs (cisplatin, mitomycin C and camptothecin). This work shows detail molecular mechanism of anti-cancer activity of ZALE and its potential for combined treatment regimens to enhance the apoptotic response of chemotherapeutic drugs.


RESULTS
ZALE induced cytotoxicity, nuclear blebbing and DNA fragmentation in HeLA cells suggesting apoptosis induction in human cervical cell line. However, the apoptosis induced was independent of caspase 3 activation and poly ADP ribose polymerase (PARP) cleavage. Further, ZALE activated Mitogen-activated protein kinases (MAPK) pathway as revealed by increased phosphorylation of extracellular-signal-regulated kinases (ERK), p38 and c-Jun N-terminal kinase (JNK). Inhibition of ERK activation but not p38 or JNK completely blocked the ZALE induced apoptosis suggesting an ERK dependent apoptosis. Moreover, ZALE generated DNA double strand breaks as suggested by the induction γH2AX foci formation. Interestingly, pretreatment of certain cancer cell lines with ZALE, sensitized the cancer cells to cisplatin and other chemotherapeutic drugs. Enhanced caspase activation was observed in the synergistic interaction among chemotherapeutic drugs and ZALE.


CONCLUSIONS
Purification and identification of the bio-active molecules from the ZALE or as a complementary treatment for a sequential treatment of ZALE with chemotherapeutic drugs might be a new challenger to open a new therapeutic window for the novel anti-cancer treatment.
Department of Biotechnology, Manipur University, Imphal, 795003, India. davis.thangjam8@gmail.com.
Thangjam Davis
TD
Singh
Department of Biotechnology, Manipur University, Imphal, 795003, India. cell.heikrujam@yahoo.com.
Heikrujam Thoihen
HT
Meitei
Department of Biotechnology, Manipur University, Imphal, 795003, India. lakhee.sharma@gmail.com.
Adhikarimayum Lakhikumar
AL
Sharma
Department of Biotechnology, Manipur University, Imphal, 795003, India. asem.robinson@gmail.com.
Asem
A
Robinson
Department of Biotechnology, Manipur University, Imphal, 795003, India. shanjulisam@gmail.com.
Lisam Shanjukumar
LS
Singh
Department of Biotechnology, Manipur University, Imphal, 795003, India. ramsing1thiyam@gmail.com.
Thiyam Ramsing
TR
Singh
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology*; D032106:Zanthoxylum / Q000737:chemistry*
D000972:Antineoplastic Agents, Phytogenic; D010936:Plant Extracts; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D002945:Cisplatin