The emerging anti-proliferative role of Nutlin-3 in the pathogenesis of systemic malignancies

Keywords: :

• Nutlin 3
• cancer
• tumor

The recent article by Zhang et al. was highly thought provoking and provided for a very interesting reading.¹ Nutlin-3 as a significant mediator of anti-carcinogenic activity in a number of systemic malignancies.

Nutlin-3 exerts anti-proliferative effects in gastric carcinomas by causing G₁ cycle arrest in tumor cells.² These anti-carcinogenic effects of Nutlin-3 are, in addition, accentuated by other chemotherapeutic agents such as cisplatin. Nutlin-3 can also be combined with liposomal doxorubicin and the combination exerts anti- proliferative effects following local application on colo-rectal carcinomas.³ In fact, Nutlin-3 exhibits synergism with liposomal doxorubicin and augments its anti-carcinogenic efficacy. Nutlin-3 also increases the sensitivity of cancerous cells in hepatocellular carcinomas to chemotherapeutic agents such as doxorubicin by virtue of altered binding of p73 and MDM2.⁴

In addition, Nutlin-3 inhibits MCP-1 and ICAM-1 and NF kappa B and thereby exerts p53-dependent anti-proliferative effects in pulmonary malignancies.⁵ Similarly, Nutlin-3, when used in conjunction with resveratrol, induces apoptosis in ovarian carcinoma cells. The anti-proliferative effects of the above combination are likely mediated by the activation of caspase.⁶

Administration of Nutlin-3 to prostate carcinoma cells is accompanied by attenuated expression of androgen receptors and simultaneous accentuation of expression of transcript p21, thus resulting in apoptosis in these cancerous cells.⁷ Interestingly, Nutlin-3 augments the sensitivity of hypoxic prostate carcinoma cells to radiotherapy by virtue of a p53-independent pathway and may thus play a major role in the management of advanced prostate malignancies in the near future.⁸ Nutlin-3 is also beneficial in the management of skin malignancies. For instance, it augments the anticancer activity in Kaposi’s sarcomas.⁹

However, patients on Nutlin-3 therapy should be carefully monitored as Nutlin-3 may cause p53 mutations and consequent development of drug resistance in cancer cells.¹⁰

Despite this, Nutlin-3 holds significant promise and along with other MDM2 inhibitors may change the very management of systemic malignancies in the near future.