Diferuloylmethane augments the cytotoxic effects of piplartine isolated from Piper chaba.
Natural compound based anticancer drug discovery is gaining interest against a wide variety of tumors. E-piplartine (trans-piplartine), a natural compound isolated from Piper chaba roots is examined against rat histiocytoma (BC-8), mouse embryonal carcinoma (PCC4), mouse macrophages (P388D1 and J774), and human neuroblastoma (IMR32) tumor cells. While Z-piplartine (cis-piplartine) failed to induce cytotoxicity (even at higher concentrations, 50 microM), E-piplartine induced a dose-dependent cytotoxicity (2-24 microM) in different tumor cells. The combinatorial treatment of piplartine with diferuloylmethane (curcumin), an anti-inflammatory and anticancer agent, significantly enhanced the piplartine induced cytotoxicity in tumor cells. Diferuloylmethane itself is not cytotoxic at 15 microM concentration; however, potentiated the piplartine induced cytotoxicity. The tumor cell killing with piplartine is preceded by G1 cell cycle arrest, and surpassed diferuloylmethane induced G2/M arrest when used in combination. In PCC4 cells, piplartine inhibited the cell cycle progression by inactivating cdk2 and destabilizing cyclin D1, whereas diferuloylmethane combination inhibited the ERK1/2 and Raf-1 signaling in addition to the inhibition of cell cycle progression. The over expression of heat shock protein 70, Hsp70 in rat histiocytic tumor cells interfered with piplartine induced cytotoxicity, hence, a cross talk between stress response and anticancer agents is presented. Our data demonstrates the biological and medicinal importance of piplartine isolated from the roots of P. chaba, and indicates that E-piplartine may be a promising candidate to use in combinatorial treatments to combat cancer.
Jyothi
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Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India.
Vanathi
P
P
Mangala Gowri
P
P
Rama Subba Rao
V
V
Madhusudana Rao
J
J
Sreedhar
A S
AS
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003474:Curcumin / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015870:Gene Expression; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D031701:Piper / Q000737:chemistry*; D010881:Piperidones / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D018517:Plant Roots; D051381:Rats; D013237:Stereoisomerism
D000972:Antineoplastic Agents, Phytogenic; D018840:HSP70 Heat-Shock Proteins; D010881:Piperidones; C498077:piperlongumine; D003474:Curcumin